key: cord-0011362-tnc3i58x
authors: Butler, Mark S.; Paterson, David L.
title: Antibiotics in the clinical pipeline in October 2019
date: 2020-03-10
journal: J Antibiot (Tokyo)
DOI: 10.1038/s41429-020-0291-8
sha: 97909c1140a84426ff0660c2f9a60bed9a4479b6
doc_id: 11362
cord_uid: tnc3i58x

The development of new and effective antibacterial drugs to treat multi-drug resistant (MDR) bacteria, especially Gram-negative (G−ve) pathogens, is acknowledged as one of the world’s most pressing health issues; however, the discovery and development of new, nontoxic antibacterials is not a straightforward scientific task, which is compounded by a challenging economic model. This review lists the antibacterials, β-lactamase/β-lactam inhibitor (BLI) combinations, and monoclonal antibodies (mAbs) first launched around the world since 2009 and details the seven new antibiotics and two new β-lactam/BLI combinations launched since 2016. The development status, mode of action, spectra of activity, lead source, and administration route for the 44 small molecule antibacterials, eight β-lactamase/BLI combinations, and one antibody drug conjugate (ADC) being evaluated in worldwide clinical trials at the end of October 2019 are described. Compounds discontinued from clinical development since 2016 and new antibacterial pharmacophores are also reviewed. There has been an increase in the number of early stage clinical candidates, which has been fueled by antibiotic-focused funding agencies; however, there is still a significant gap in the pipeline for the development of new antibacterials with activity against β-metallolactamases, orally administered with broad spectrum G−ve activity, and new treatments for MDR Acinetobacter and gonorrhea.

Since their development in the 1940s, antibacterial drugs have become lifesaving medicines that are integral to human health. Unfortunately, antibacterial drug resistance is widespread amongst pathogenic bacteria, which significantly reduces the medical effectiveness of currently marketed drugs. These drug-resistant and multi-drug resistant (MDR) bacteria have been acknowledged by Governments and scientists as one of the world's most pressing health issues; however, the discovery and development of new antibiotics and antibiotic-alternatives to treat these infections is not straightforward. As a consequence, it is important to analyze the antibacterial development pipeline to capture a snapshot of what is happening today and compare it to previous years. This review provides an update to previous reviews in this series in 2015 [1] , 2013 [2] and 2011 [3] , which are complementary to recent reviews that describe the pre-clinical [4] and clinical pipeline [5] [6] [7] [8] [9] [10] [11] . There have also been several important reviews that analyze the lead discovery and development of antibiotics [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] , antibiotic alternatives [23] [24] [25] , β-lactam/ β-lactamase inhibitors [26, 27] , and antibiotic conjugate and prodrug strategies [28] . There has also been reviews that discuss issues with antibiotic stewardship, resistance and, the commercialization challenge [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] .

This review details antibacterials launched since 2009 (Table 1; Table S1 from 2000 to 2009) and analyzes new antibacterials approved (Figs. 1-3) since the previous 2015 review [1] . Small molecule antibacterials, BLI combinations, and antibody drug conjugates (ADC) that are being evaluated in phase-I, -II, or -III clinical trials and under pre-approval regulatory evaluation as of 31 October 2019 (Tables 2-5, Figs. [4] [5] [6] [7] [8] [9] [10] [11] [12] are reviewed highlighting their development status, mode of action, spectra of activity, historical discovery, and origin of the lead compound's pharmacophore. The clinical trial codes, which are predominantly from ClinicalTrials.gov (NCT), are listed in parentheses for each antibacterial, BLI β-lactamase inhibitor, DBO diazabicyclooctane, mAb monoclonal antibody, NP natural product-derived, S synthetic, USA United States of America a The structures of the antibiotics approved from 2000 to 2014 can be found in our previous reviews [1] [2] [3] b First member of a new antibiotic or β-lactamase inhibitor class approved for human therapeutic use c Approved for topical use d First launches: tazobactam in 1992, ceftazidime in 1983, meropenem (13) in 1998, and imipenem (15) + cilastatin (16) in 1985 e Also approved for the treatment of amebiasis and trichomoniasis while non-registered trials are referenced at least by a Press Release or peer-reviewed publication. A list of online clinical trial databases can be found in the Supplementary information. Repurposed drugs that have not previously been approved as antibacterials have been included in this analysis. Pro-drugs are grouped together with their active metabolites, while ongoing trials of antibacterial drugs that already approved anywhere in the world are not discussed but are listed in Table S2 . Compounds for which no development activity has been reported since 2017 are listed in Table 6 . The antibacterials in clinical development have been further analyzed by phase and source derivation (Fig. 13) and to the previous 2011 [3] , 2013 [2] , and 2015 [1] (Table 7 , Figs. 15 and 16) and administration routes (Figs. S1 and S2) has also been undertaken.

Data in this review were obtained by analyzing the scientific literature and internet resources such as company web pages, clinical trial registers, The Pew Charitable Trusts (Philadelphia, PA, USA) [42, 43] and World Health Organization (WHO) (Geneva, Switzerland) pipeline analyses [5] and biotechnology newsletters. Every effort has been undertaken to ensure that these data are accurate; however, it is possible compounds in the earlier stages of clinical development have been overlooked as there is limited information available in the public domain. An overview of the drug development and approval process, antibiotic clinical trial categories and abbreviations can be found in the Supplementary information.

Since 2000, 38 new antibacterials (two NP, 16 NP-derived and 20 synthetic-derived), four new β-lactam/BLI combinations and three monoclonal antibodies (mAbs) have been launched worldwide (Tables 1 and S1, Figs. 1 and 2). Of the 38 new antibacterials, five were first-in-class: linezolid (oxazolidinone, S, 2000), daptomycin (lipopeptide, NP, 2003), retapamulin (pleuromutilin, NP-derived, 2007), fidaxomicin (tiacumicin, NP, 2011) and bedaquiline (diarylquinoline, S, 2012). These five antibacterials have Gram-positive (G+ve) activity only; however, bedaquiline is noteworthy as it was the first new drug class approved for tuberculosis (TB) since 1963 [44] . Although the approval of a new class of G-ve antibacterial is still elusive, there has been two new BLI classes launched (diazabicyclooctane (DBO)-BLI (avibactam, S, 2015) and boron-type BLI (vaborbactam (12) , S, 2017)) that have activity in combination with β-lactams against G-ve bacteria. Two of the approved mAbs, raxibacumab [ 

Since the 2016, seven new antibacterials (Fig. 2) and two new β-lactam/BLI combinations (Fig. 3 ) have been approved around the world. These new approvals are discussed, along with morinidazole (1) and zabofloxacin (2), which were not detailed in the previous review [1] .

Morinidazole (1) 57] , and drug-resistant Neisseria gonorrhoeae [58] . There is ongoing development for the treatment of [59] . Dong Wha has licensing and supply agreements with China and 12 Middle Eastern and North African countries [60] .

Delafloxacin (3) (Baxdela, RX-3341, WQ-3034, ABT-492) [61, 62] , which is a fluoroquinolone that was being developed by Melinta Therapeutics (New Haven, CT, USA), was approved by the U.S. Food and Drug Administration (FDA) in June 2017 for the treatment of acute bacterial skin and skin structure infections (ABSSSI) using both intravenous (IV) and oral formulations [63] . In addition to activity against G+ve bacteria, delafloxacin (3) is also approved for the treatment of the following G−ve bacteria: Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa [64] ; however, 3 is rarely used to treat these G−ve pathogens due to resistance. In October 2019, Melinta announced that the FDA had approved an sNDA for 3 for the treatment of community-acquired bacterial pneumonia (CABP) [65] .

Plazomicin (4) (Zemdri, ACHN-490), which is a semi-synthetic derivative [66] [67] [68] of the aminoglycoside sisomicin [69, 70] developed by Achaogen, Inc. (South San Francisco, CA, USA). An IV formulation of 4 was approved by the FDA in June 2018 for the treatment of cUTI, including pyelonephritis, due to certain Enterobacteriaceae where treatment options are limited [71] . At the same time, Achaogen also sort the approval of plazomicin (4) to treat bloodstream infection (BSI), but the FDA indicated further trials would be required to demonstrate its effectiveness. Achaogen had submitted an marketing authorization application (MAA) in October 2018 with The European Medicines Agency (EMA) for complicated urinary tract infections (cUTI), including pyelonephritis, BSI due to certain Enterobacteriaceae, and Enterobacteriaceae in patients with limited treatment options [72] . However, in April 2019, Achaogen filed for bankruptcy [73] and it was announced in June 2019 that Cipla USA Inc. (Sunrise, FL, USA) had purchased the worldwide rights to plazomicin (4) except for China where the rights were held by QiLu Antibiotics Pharmaceutical Co. (Jinan, People's Republic of China) [74] .

Eravacycline (5) (Xerava, TP-434), which is an IV administered, synthetic fluorocycline-type tetracycline derivative [75] [76] [77] developed by Tetraphase Pharmaceuticals (Watertown, MA, USA), was approved for treatment of complicated intra-abdominal infections (cIAI) by the EMA in July 2018 [78] and by the FDA in August 2018 [79, 80] . Eravacycline (5) had also been evaluated in a cUTI phase-III trial (NCT01978938) but did not achieve statistical non-inferiority to ertapenem and no further development is likely [81] .

Omadacycline (6) (Nuzyra, amadacycline, PTK-0796) [82] , which a semi-synthetic minocycline derivative developed by Paratek Pharmaceuticals (Boston, MA, USA) with both oral and IV administration, was approved by the FDA in October 2018 for the treatment CABP and ABSSSI [83] [84] [85] . As a ten-year European market exclusivity starts after a product's first approval, Paratek has decided to resubmit their MAA for CABP and ABSSSI after the completion of their post-marketing CABP study for the FDA; this is because the EMA required an addition CABP study Structure not publically disclosed c SPR741 (52) will be used in combination with other antibiotics in subsequent development but voted to approve 6 for ABSSSI [86] . Omadacycline (6) is also being evaluated in phase-II trials as a treatment of acute pyelonephritis (NCT03757234) and cystitis (UTI, NCT03425396). Sarecycline (7) (Seysara, WC-3035, P005672, PTK-AR01) was approved by the FDA in October 2018 as a topical treatment of moderate to severe acne [87] [88] [89] [90] . Sarecycline (7) is a semi-synthetic tetracycline derivative discovered by Paratek Pharmaceuticals (Boston, MA, USA) and developed by Allergan, plc (Dublin, Ireland), which had its US dermatology assets acquired by Almirall S.A. (Barcelona, Spain) in August 2018.

Pretomanid (8) (PA-824) is a nitroimidazole [53] derived from CGI-17341 [91] that was approved by the FDA in August 2019 as an orally-administered treatment for extensively drug resistant (XDR)-TB in combination with bedaquiline and linezolid under the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) [92] . The Global Alliance for TB Drug Development (TB Alliance) (New York, NY, USA) has been evaluating pretomanid (8) in three phase-III trials: in combination with linezolid and bedaquiline (NCT03086486), linezolid (NCT02333799), and linezolid, bedaquiline, moxifloxacin and clofazimine (NCT02589782). A phase-III in combination with moxifloxacin and pyrazinamide was completed in May 2018 (NCT02342886). Pretomanid (8) acts as prodrug that is reductively activated by the deazaflavin (cofactor F 420 )-dependent nitroreductase Rv3547 [93] [94] [95] . Pretomanid (8) inhibits cell wall growth in aerobic conditions by hindering mycolic acid formation, while its activity involves the induction of respiratory poisoning under anaerobic conditions [93] [94] [95] . A recent report has also implicated the production of methylglyoxal using an untargeted metabolomics approach [96] .

Lefamulin (9) (Xenleta, BC-3781) is a semi-synthetic pleuromutilin [97] [98] [99] derivative developed by Nabriva Therapeutics AG (Vienna, Austria) that was approved by the FDA in August 2019 as a treatment for patients with CABP [100] . Nabriva has also submitted an MAA for lefamulin (9) to the EMA in June 2019 [101] . Lefamulin (9) has had both oral and IV formulations approved, which should lead to shorter hospital stays, and is the second pleuromutilin derivative approved for human use but the first that can be systemically administered. The first approved pleuromutilin in 2007 was retapamulin, which is a topical treatment for impetigo [97, 98] . Taniborbactam (72) Like other pleuromutilins, lefamulin (9) inhibits bacterial protein synthesis and has activity against a range of skin [102] , respiratory [103, 104] and sexually transmitted pathogens [105] . Lascufloxacin (10) (Lasvic, KRP-AM1977) is a fluoroquinolone with broad-spectrum activity [106, 107] that was developed by Kyorin Pharmaceutical Co., Ltd (Tokyo, Japan). In September 2019, Kyorin announced that an oral formulation of 10 (called KRP-AM1977X) has been approved for the treatment of CAP, otorhinolaryngological and respiratory tract infections [108] , while an NDA for the IV formulation (KRP-AM1977Y) is under preparation. Cefiderocol (11) (Fetroja, S-649266) is an IV administered, semi-synthetic cephalosporin-type β-lactam developed by Shionogi & Co., Ltd. (Osaka, Japan), which incorporates a catechol siderophore that facilitates active transport into the bacteria via iron transporters, that has activity against MDR G-ve pathogens including carbapenemase producers [109] [110] [111] [112] . Cefiderocol (11) is first approved antibacterial that exploits the iron transport uptake mechanism. Shionogi filed an NDA with the FDA in December 2018 for cUTI including pyelonephritis and an MAA with EMA in March 2019 multi-drug G-ve infections [113] . In November 2019, the FDA approved cefiderocol (11) for the treatment of cUTI [114] . Cefiderocol (11) has been evaluated in phase-III trials as a treatment for carbapenem-resistant G-ve pathogens at various sites (NCT02714595) and hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP)/healthcare-associated pneumonia (HCAP) (NCT03032380). Positive results for a phase-II trial against cUTI (NCT02321800) has recently been published [115] .

Vabomere is an IV administered combination of the first-inclass boronate-type BLI, vaborbactam (12) (RPX7009), and meropenem (13) that was discovered by Rempex Pharmaceuticals. Rempex were acquired by The Medicines Company (Parsippany, NJ, USA) in December 2013, who were granted FDA approval in the August 2017 for the treatment of G-ve cUTIs (E. coli, K. pneumoniae and E. cloacae species complex), including pyelonephritis [116, 117] . Soon after this approval, The Medicines Company sold its anti-infective business units to Melinta Therapeutics (New Haven, CT, USA) [118] . In November 2017, the EMA approved Vabomere for the treatment of patients with cIAI, HAP/VAP, bacteremia, and other aerobic G-ve organisms with limited treatment options [119] . Vaborbactam (12) is noteworthy for its rapid movement from Rempex's 8 August 2011 patent filing [120] to its first approval in just over six years on 29 August 2017 (Table 1, Fig. 3) .

Recarbrio, which is a combination of the relebactam (14) , imipenem (15) and cilastatin (16) July 2019 as an IV administered treatment of cUTI and cIAI [117, [121] [122] [123] . Relebactam (14) is a DBO-type BLI [124] that is administered with the imipenem (15) , which is a carbapenem first launched in 1987, and cilastatin (16) , which is a dehydropeptidase inhibitor that improves the in vivo stability of imipenem (15) [125] .

The compounds currently undergoing clinical trials or under regulatory evaluation for the treatment of bacterial infections as of the end of October 2019 are detailed in the following tables and figures: NDA and phase-III in Tables 2 Table 3 with structures in Figs. 6 and 7, and phase-I in Tables 4 and 5 Compounds in NDA/MAA filing Solithromycin (17) (T-4288, CEM-101) is a semi-synthetic 2-fluoroketolide [126] that is being evaluated by FUJIFILM Toyama Chemical Co., Ltd. (Tokyo, Japan) in several phase-III trials in Japan as an oral treatment for sinusitis (JPRN-JapicCTI-173733), otorhinolaryngological (head and neck) infections (JPRN-JapicCTI-163467), respiratory tract infections (JPRN-JapicCTI-163438) and CAP (JPRN-JapicCTI-163439). The National Institute of Allergy and Infectious Diseases (NIAID) (Bethesda, MD, USA) has also been evaluated 1 in a phase-I trial for gonorrhea (NCT02348424). In April 2019, FUJIFILM Toyama applied for a NDA in Japan with the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) as a treatment bacterial infections in otorhinolaryngology (ear, nose and throat) [127] . Solithromycin (17) was discovered by Optimer Pharmaceuticals (San Diego, CA, USA) and was being developed in the USA by Cempra Pharmaceuticals (Chapel Hill, NC, USA). Cempra submitted an NDA for CABP to the FDA in May 2016 but the FDA sent a Complete Letter Response in December 2016 that requested additional clinical safety information and the satisfactory resolution of manufacturing facility inspection deficiencies [128] . Cempra withdrew the CABP MAA for the EMA in March 2017 [129] . Cempra merged in August 2017 with Melinta Therapeutics (New Haven, CT, USA), who are not currently developing solithromycin (17) ( Table 2 , Fig. 4 ).

Iclaprim (18) is an IV and orally dosed trimethoprim analog that was being developed by Motif Bio plc (London, UK) [130, 131] . Iclaprim (18) was discovered by Roche (Basel, Switzerland; coded RO-48-2622) and licensed in 2001 to their anti-infectives spin-out Arpida AG (Reinach, Switzerland; coded AR-100). Arpida completed two phase-III trials evaluating 18 for SSSI but the FDA rejected their NDA in 2009, while their MAA was later withdrawn due to concerns about not reaching non-inferiority to its comparator antibiotic and potential QT interval prolongation issues [132] . Motif Bio started to develop iclaprim (18) in 2015 and submitted an NDA with the FDA in June 2018 for ABSSSI from data derived from two phase-III trials (NCT02600611 and NCT02607618) [133] with altered dosing regimens compared with Arpida's trials [131] ; however, the FDA required an additional clinical trial before granting approval [134] and Motif Bio have subsequentially halted development. Compounds in phase-III trials Sulopenem (19) (CP-70,429) is a synthetic thiopenem β-lactam discovered in Pfizer's Japanese laboratories that underwent clinical evaluation in the mid-1990s but development was discontinued due to high development costs and market return concerns [135] . Interestingly, the R enantiomer of sulopenem caused unpleasant sulfurous odors when dosed in human volunteers and the racemate CP65,207 could not be used [136] . Pfizer re-started clinical development in 2003 using a more efficient production-scale synthesis procedure to help alleviate the cost issue [137, 138] . In late 2015, Iterum Therapeutics plc (Dublin, Ireland) licensed sulopenem (19) and its prodrug sulopenem etzadroxil (20) (PF-03709270) from Pfizer [139] . Iterum are now evaluating 19 using IV administration followed by oral dosing of 20 in phase-III studies for the treatment of cIAI (NCT03358576) and cUTI Table 6 Compounds discontinued or likely to have been discontinued from clinical development since 2016 or previous review [1] Name (synonym)

Compound class (lead source); mode of action Last known status and indication In these trials, sulopenem etzadroxil (19) is administered along with probenecid (21) [140] , which is a marketed drug for gout and hyperuricemia that increases uric acid production, that inhibits the tubular secretion of some β-lactams and leads to a longer drug half-life and higher serum concentrations [141] (Table 3 , Figs. 6 and 7). Murepavadin (22) (POL7080, RG7929) is a synthetic cyclic peptide 14-mer based on protegrin I that is being developed by Polyphor, Ltd. (Basel, Switzerland) [142] [143] [144] . Murepavadin (22) has a new mode of action through binding to the N-terminal of the β-barrel protein LptD (Imp/OstA) from P. aeruginosa [142, 145] , which affects lipopolysaccharide transport to the cell surface and leads to bacterial death [146] . As this binding pocket is only present in P. aeruginosa LptD, murepavadin (22) displays selective anti-P. aeruginosa activity, which should help to reduce resistance and microbiome disturbance. Polyphor have been evaluating murepavadin (22) in two phase-III trials for the treatment of Pseudomonas nosocomial pneumonia (NCT03582007) and VAP infections (NCT03409679); however, it was announced in May 2019 that there was an increase in serum creatinine and acute kidney injury using IV administration in the nosocomial pneumonia trial [147] . In July 2019, Polyphor announced that this trial had been closed but stressed that the inhaled administration route was not impacted [148] . SQ 109 (23) is an ethambutol analog discovered at the NIAID (Bethesda, MD, USA) [149, 150] that was first developed by Sequella, Inc (Rockville, MD, USA), who later licensed the development for the Russian Federation and Commonwealth of Independent States to Infectex (Moscow, Russia). In March 2017, Infectex announced positive results from a phase-II/III trial for the treatment of MDR pulmonary TB [151, 152] , but since then there has been no update. Results from a Sequella-sponsored phase-II trial evaluating high range oral doses of rifampicin, moxifloxacin and SQ109 (23) for treating TB (NCT01785186) has been published [153] . Although SQ109 (23) is structurally derived from ethambutol, SQ109 (23) has different modes of action and activity against other bacteria and parasites. Ethambutol targets arabinofuranosyl transferases EmbA and EmbB [154, 155] , which are involved in cell wall synthesis, and was recently reported to show synergy with isoniazid targeting a transcriptional repressor of the inhA gene [156] and glutamate racemase (MurI) [157] . Conversely, SQ109 (23) has been reported to inhibit mMpl3, which is a trehalose monomycolate transporter important in cell wall synthesis [158] , as well as inhibit the quinone biosynthesis enzymes MenA and MenG and affect bacterial respiration and electron transfer [159, 160] .

Ridinilazole (24) (SMT19969) is a synthetic bis-benzimidazole [161] that is being developed by Summit Therapeutics plc (Oxford, UK). Ridinilazole (24) will be evaluated in two phase-III trials as for the treatment of CDI compared with vancomycin (NCT03595553 and NCT03595566) with assistance from the Biomedical Advanced Research and Development Authority (BARDA) (Washington DC, USA), which is an office of the U.S. Department of Health and Human Services [162] . The mode of action of 24 has not been fully elucidated but has been shown to affect cell division [163] . Importantly, ridinilazole (24) has been shown to reduce toxin production [163] and be less harsh on the gut microbiome compared with vancomycin [164] .

Gepotidacin (25) (GSK-2140944) is an orally bioavailable, first-in-class antibacterial (triazaacenaphthylene class), which is new type of bacterial Type II topoisomerase inhibitor [165] , being developed by GlaxoSmithKline (GSK) (London, UK) that has just started phase-III trials as a treatment for uncomplicated UTI (NCT04020341) and uncomplicated urogenital gonorrhea (NCT04010539). Gepotidacin (25) has previously completed three phase-II clinical trials: G+ve ABSSSI (NCT02045797), uncomplicated urogenital gonorrhea caused by N. gonorrhoeae (NCT02294682) [166, 167] and uncomplicated UTI (NCT03568942). Gepotidacin (25) has activity against range of both G+ve and G−ve pathogens [168] [169] [170] , including several species associated with sexually transmitted infections (STIs) such as N. gonorrhoeae [166, 171] , Mycoplasma, and Ureaplasma [172] . Zoliflodacin (26) (ETX0914, AZD0914) is the first member of a new class of topoisomerase inhibitor class [173] called the spiropyrimidinetriones being developed by Entasis Therapeutics (Waltham, MA, USA) that has started a phase-III trial (NCT03959527) as an orally administered treatment of uncomplicated gonorrhea [174] in collaboration with the Global Antibiotics Research and Development Partnership (GARDP) (Geneva, Switzerland). Zoliflodacin (26) also has activity against Mycoplasma genitalium, which could enhance its usefulness in treating STIs [175] . Entasis completed a phase-II trial (NCT02257918) that showed that zoliflodacin (26) was able to successfully treat uncomplicated urogenital and rectal gonococcal infections but was less efficacious against pharyngeal infections [176] .

Contezolid (27) (MRX-I) is an oxazolidinone being evaluated by MicuRx Pharmaceuticals (Hayward, CA, USA and Shanghai, People's Republic of China) [177] . MicuRx announced positive results for a China-based phase-III trial for cSSTI and they plan to file an NDA with the Chinese [178] . Contezolid (27) has completed a phase-II trial against ABSSSI (NCT02269319) using oral dosing. Contezolid (27) was selected for development due to a proposed superior safety profile compared with linezolid [177] and promising activity against G+ve bacteria [179, 180] and TB [181] . The prodrug of contezolid (27), contezolid acefosamil (28) (MRX-4) [182] , is being evaluated in a phase-II trial for the treatment of ABSSSI in both China and the USA (NCT03747497) using an IV to oral switch route. Levonadifloxacin (29) (WCK-771) and its alanine prodrug alalevonadifloxacin (30) (WCK-2349) [183] are currently being evaluated in a phase-III trial for CSSSI in India [184, 185] using IV and oral administration. Levonadifloxacin (29) is the arginine salt of the fluoroquinolone S-(-)nadifloxacin [186] [187] [188] ; racemic nadifloxacin has been topically used to treat acne and MRSA [186] .

Compounds in phase-II trials BOS228 (31) (LYS228) is an IV-administered monobactam with potent activity against both serine and metalloβ-lactamase expressing [189] discovered by Novartis (Basel, Switzerland) [190] [191] [192] . Novartis started phase-II trials of BOS228 (31) for G−ve cUTI (NCT03377426) and cIAI (NCT03354754); however, after Novartis exited antibiotic development in July 2018, these trials were halted and 31 was licensed to Boston Pharmaceuticals (Cambridge, MA, USA) for further development [193] (Table 3 , Figs. 6 and 7) .

Benapenem (32) is a carbapenem, which is structurally similar to ertapenem and shares its longer half-life compared with other carbapenems, that is currently being evaluated phase-II trial as a treatment for a cUTI including pyelonephritis by Sihuan Pharmaceutical (Beijing, People's Republic of China) using IV administration (CT20181302) [194] . Benapenem (32) has completed three phase-I trials (NCT03570970, NCT03578588, and NCT03588156) and results from these trials indicated that 32 was well tolerated and the PK data supported oncedaily IV dosing [195] . Nafithromycin (33) (WCK 4873) is an orally bioavailable ketolide being developed by Wockhardt Limited (Mumbai, India) that completed a CABP phase-II trial (NCT02903836) in July 2017. Nafithromycin (33) recently started a new multiple dosing phase-I trial (NCT03981887) and has activity against both G+ve (e.g., S. pneumoniae and Staphylococcus aureus) and G−ve (e.g., Haemophilus influenzae, Moraxella catarrhalis, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae) bacteria [196, 197] .

MGB-BP-3 (34) is a DNA binding antibacterial being developed by MGB Biopharma (Glasgow, UK) that recently started a phase-II trial for the treatment of patients with C. difficile-associated diarrhea (CDAD) (NCT03824795). MGB-BP-3 (34) was first synthesized at the University of Strathclyde (Glasgow, UK) and its structure is based on the actinomycetes-derived minor groove binders the distamycin, netropsin and thiazotropsin ("lexitropsins") [198] .

XF-73 (35) (exeporfinium chloride) is a topically administered, photosensitizing porphyrin with derivative broad spectrum G+ve activity [199] [200] [201] [202] that is being developed by Destiny Pharma (Brighton, UK). XF-73 (35) has recently started a phase-II trial to study its effect on nasal S. aureus in patients at risk of post-operative staphylococcal infections (NCT03915470). XF-73 (35) has been evaluated in phase-I/II trials for the prevention of postsurgical staphylococcal nasal infections (NCT02282605) and positive data from a phase-I trial have been reported (NCT01592214) [203] .

TNP-2092 (36) (CBR 2092) is currently being developed by TenNor Therapeutics (Suzhou, People's Republic of China) in a phase-II trial for the treatment of G+ve ABSSSI infections using IV dosing (NCT03964493). TenNor are also evaluating TNP-2092 (36) against catheter-related bloodstream infections and prosthetic joint infections [204] . TNP-2092 (36) is a rifamycin-quinolizinone hybrid antibacterial discovered by Cumbre Pharmaceuticals [205] that had excellent activity against G+ve pathogens [206] . The rifamycin lead was rifampicin, while the quinolizinone component lead was ABT-719, which had a similar activity profile to quinolones [205] . It was shown that the G+ve antibacterial activity of 36 was via the modes of action of the hybrid components: RNA polymerase (rifamycin) and balanced DNA gyrase and DNA topoisomerase IV (quinolone) inhibition [207] .

ATx201 is a topical formulation of niclosamide (37), which is a halogenated salicylanilide derivative being developed by UNION Therapeutics A/S (Hellerup, Denmark; previously called AntibioTx) [208, 209] . Niclosamide (37) was discovered in the late 1950s by Bayer (Leverkusen, Germany) and is currently used an anthelmintic, predominantly to treat tapeworm infections [210] . ATx201 completed phase-II trials in 2018 for the treatment for impetigo (NCT03429595) and atopic dermatitis (NCT03304470) with its future development being focused on atopic dermatitis (EudraCT2019-002771-33) [211] . In addition to bacterial infections [212] [213] [214] [215] , there have also been efforts to "re-purpose" 37 as a treatment for Parkinson's disease, Type 2 diabetes, viral infections and oncology [216, 217] . Niclosamide (37) has multiple mechanisms in these therapeutic areas [216] . In bacteria, there is evidence that 37 interferes with oxidative phosphorylation in TB, which could affect membrane potential and pH homeostasis [218] , and inhibit P. aeruginosa quorum sensing [219] .

Auranofin (38) , which is a 2,3,4,6-tetra-O-acetyl-1-thioβ-D-glucopyranosato-[triethylphosphine] gold complex first approved as a rheumatoid arthritis drug in 1985 [220] [221] [222] , is currently being evaluated in a phase-II trial by The Aurum Institute (Johannesburg, Republic of South Africa) as an adjunctive host directed therapies to assess its potential to shorten TB treatment and/or prevent permanent lung damage (NCT02968927). Auranofin (38) primarily exerts its biological activity through inhibition of thioredoxin reductase [223] [224] [225] but its mode of action in bacteria is more complex [226] [227] [228] . There has also been interest in re-purposing auranofin (38) for C. difficile [229] , Helicobacter pylori [230] , and MRSA, S. pneumoniae and Enterococcus faecalis [223, 226, 231, 232] .

MBN-101 (39) (bismuth ethanedithiol, BisEDT) has broad spectrum, topical antibacterial and antibiofilm activity, and is being developed by Microbion Corporation (Bozeman, MT, USA) [233, 234] . MBN-101 is currently being evaluated in a phase-II trial patients diagnosed with an orthopedic infection (NCT02436876), and a phase-Ib/IIa trial as a topical treatment for diabetic foot infection (NCT02723539). Microbion licensed MBN-101 to Haisco Pharmaceutical Group (Chengdu, People's Republic of China) for development in China in February 2016 [235] . Bismuth has some intrinsic antibacterial activity as demonstrated by bismuth subsalicylate (later called Pepto Bismol ® ), which has been used since 1900 to help treat stomachaches and traveler's diarrhea [236] , and Xeroform ® , which is a petrolatum-based fine mesh gauze containing 3% bismuth tribromophenate [237] . Bismuth is also used in combinations with other antibiotics and a proton pump inhibitor to treat H. pylori infections [238] .

Afabicin (40) (Debio 1450, AFN 1720), which is a prodrug of afabicin desphosphono (41) (Debio 1452, AFN-1252), is being evaluated by Debiopharm Group (Lausanne, Switzerland) in a phase-II trial (NCT03723551) using an IV/oral switch strategy for the treatment of S. aureus bone or joint infection [239] . Afabicin (40) had previously completed another phase-II ABSSSI trial (NCT02426918). Afabicin (40) specifically inhibits staphylococcal FabI [240, 241] , which is an essential enzyme in the final step of the fatty acid elongation cycle [242, 243] , and the initial lead was discovered [244, 245] by GSK (London, UK) and further developed [246] by Affinium Pharmaceuticals (Austin, TX, USA) before licensing to Debiopharm.

OPS-2071 (structure not disclosed) is a quinolone-based antibacterial being developed by Otsuka Pharmaceutical (Tokyo, Japan) that has completed a phase-II trial against C. difficile and enteric infections (NCT02473393) [247] . In February 2019, Otsuka announced an additional phase-II trial evaluating OPS-2071 as an add-on therapy for Crohn's disease where patients show symptoms of active inflammation during ongoing treatment (NCT03850509). Delpazolid (42) (RMX2001, LCB01-0371) is an oxazolidinone discovered by LegoChem Biosciences, Inc. (Daejeon, Republic of Korea), which has activity against G+ve bacteria [248] , TB [249] and Mycobacterium abscessus [250] , that is being evaluated in a phase-II trial for the treatment of TB using oral administration (NCT02836483). Delpazolid (42) is being co-developed in China with HaiHe Biopharma (Shanghai, People's Republic of China) and China Shijiazhuang Holding Group Co (Hong Kong, People's Republic of China) [251] .

Sutezolid (43) (PF-2341272, PNU-100480) [252] is an oxazolidinone-type antibacterial that was originally developed alongside linezolid by Upjohn & Co (later Pharmacia & Upjohn), which was later absorbed into Pfizer (New York, NY, USA) in 1995. Sutezolid (43) has potent activity against TB [253] [254] [255] and Sequella (Rockville, MD, USA) licensed 43 from Pfizer in 2013 and a phase-II trial was completed as a treatment for naive patients with drug-sensitive pulmonary tuberculosis using oral administration (NCT01225640) [256] . Sequella and the TB Alliance (New York, NY, USA) have recently started a phase-II trial evaluating sutezolid (43) in combination with bedaquiline, delamanid, and moxifloxacin against a combination of bedaquiline, delamanid, and moxifloxacin (NCT03959566).

DNV-3837 (44) (MCB-3837) is an oxazolidinonequinolone hybrid prodrug of DNV-3681 (45) (MCB-3681) developed by Morphochem AG/Biovertis AG, which was acquired in 2018 by Deinove (Montpellier, France) . that recently started a phase-II trial as a potential treatment of CDI (NCT03988855) [257] . DNV-3837 (44) is administered intravenously, which differentiates it from other antibacterials being developed for CDI that are delivered orally with little or no systemic distribution (po topical). DNV-3837 (44) shows activity against G+ve bacteria including MRSA, C. difficile, Francisella tularensis, and Bacillus anthracis [258] [259] [260] [261] .

Telacebec (46) (Q203) is an orally bioavailable imidazo [1,2-a]pyridine amide [262, 263] that is currently being developed by Qurient Co., Ltd. (Seongnam-si, Republic of Korea) in a phase-II trial for treatment of TB (NCT03563599). The imidazo[1,2-a]pyridine amide pharmacophore was identified during phenotypic high-content assay in infected macrophages and inhibits TB growth via targeting QcrB, which is a subunit of the menaquinol cytochrome c oxidoreductase (bc 1 complex) [262, 264, 265] . Infectex (Moscow, Russia), who has licensed 46 from Qurient, announced the successful completion of a Russian phase-I trial in June 2017 [266] .

Macozinone (47) (PBTZ169) is a benzothiazinone (BTZ) derivative being evaluated by Nearmedic Plus LLC (Moscow, Russia) in a phase-II trial for the treatment of TB in Russia and Belarus but the trial was discontinued due to slow enrollment in February 2018 (NCT03334734).

The Innovative Medicines for Tuberculosis (iM4TB) Foundation (Lausanne, Switzerland) is leading the development in the rest of the world and are currently evaluating oral dosing of macozinone (47) in a phase-I trial (NCT03776500). Macozinone (47) is a second generation BTZ043 (48; Fig. 8 ) analog, which had potent in vitro activity against TB but suboptimal in vivo efficacy, that has enhanced physico-chemical properties [267] ; however, macozinone (47) still has relatively poor solubility, which could affect oral bioavailability [268] . The nitro group present BTZs is reduced in vivo and the reactive nitroso intermediate forms a covalent semi-mercaptal adduct with cysteine-387 of Mycobacterium tuberculosis decaprenylphosphoryl-β-D-ribose (DPR) 2′-oxidase (DprE1), which is an essential enzyme used to cell wall synthesis [269] [270] [271] . Macozinone (47) has activity against a range of Mycobacterium species but resistance can arise through amino acid polymorphism of cysteine-387 [271, 272] . It has been recently shown that macozinone (47) and BTZ043 (48) can be de-aromatized in vivo through formation of a Meisenheimer complex, which could also reduce their in vivo half-lives [273] .

OPC-167832 (49) is an orally bioavailable 3,4-dihyrdocarbostyril derivative being developed by Otsuka Pharmaceutical (Tokyo, Japan) as a potential treatment for uncompleted pulmonary TB in a phase-I/II trial (NCT03678688) [274, 275] . OPC-167832 (49) exerts its antimycobacterial activity through inhibition of cell wall synthesis target DprE1 [274] , which is the same target as the BTZ-043 (48) and macozinone (47) [269, 273, 276] . GSK656 (50) (GSK3036656) is a boron containing leucyl t-RNA synthetase inhibitor [277, 278] being developed by GSK (London, UK) that is currently being evaluated in a phase-II trial as a treatment for patients with drugsensitive pulmonary TB using oral dosing (NCT03557281). GSK3036656 (50) was discovered in collaboration with Anacor Pharmaceuticals (Palo Alto, CA, USA), who had identified that 3-aminomethylbenzoxaboroles inhibit leucyl-tRNA synthetase [277, 279] . The closely related epetraborole (AN3365, GSK 2251052), which is the dechloro-derivative GSK656 (50), entered phase-II clinical trials in 2012 but was discontinued to the rapid emergence of resistance [280, 281] .

Compounds in phase-I trials TP-6076 (structure not disclosed) is an IV administered, fully synthetic fluorocycline (tetracycline class) being developed by Tetraphase Pharmaceuticals (Watertown, MA, USA) that is being evaluated in a phase-I trial (NCT03691584). TP-6076 has shown promising activity against carbapenem-resistant Acinetobacter baumannii clinical isolates [282] and Tetraphase has received support from CARB-X (Boston, MA, USA) to help with development [283] (Table 4 , Figs. 8-10) .

TP-271 (51) is another fully synthetic fluorocycline being developed by Tetraphase Pharmaceuticals (Watertown, MA, USA) that completed two phase-I trials investigating oral administration (NCT03450187 and NCT03024034) and two phase-I trials evaluating IV administration (NCT02724085 and NCT03234738). TP-271 (51) has activity against G +ve and G −ve pathogens associated with respiratory tract infections [284] and the biothreat pathogens F. tularensis [285] and B. anthracis [286] .

SPR 741 (52) (NAB 741), which is a polymyxin derivative with antibiotic potentiating activity being developed by Spero Therapeutics (Cambridge, MA, USA), has completed two phase-I trials (NCT03022175 and NCT03376529). SPR 741 (52) will need to be partnered with another antibacterial and be administered using an IV route to show clinical effect. The mode of action of polymyxins involves membrane disruption but is complex [287] . SPR 741 (52) was initially developed by Northern Antibiotics (Helsinki, Finland) and designed to have less nephrotoxicity by reducing the number of positive charges [288] [289] [290] . The replacement of the 3-hydroxyoctanoate group with an acetate leads to a significant reduction in antibacterial activity, while maintaining Lipid A binding in a similar way to polymyxin nonapeptide; the combination of these effects leads to strong synergisms and enhanced G-ve activity of several antibacterials [290] [291] [292] [293] .

SPR 206 (53) is an IV administered polymyxin derivative [294] with activity against MDR G-ve bacteria being developed by Spero Therapeutics (Cambridge, MA, USA) that has recently started a phase-I trial (NCT03792308). In January 2019, Spero announced that Everest Medicines (Shanghai, People's Republic of China) had licensed SPR 206 (53), along with an exclusive option to rights to SPR741 (52), in China, South Korea and several Southeast Asian countries [295] .

GT-1 (54) (LCB10 0200) is an IV administered cephalosporin siderophore β-lactam being developed by Geom Therapeutics (San Francisco, CA, USA), which is a joint venture with LegoChem Biosciences (Seoul, Republic of Korea). GT-1 (54) started a phase-I trial (ACTRN12618001980224) in Australia in March 2019 but the trial has been stopped due to safety concerns. There has been no subsequent update about whether development will continue. Apramycin (55) is an aminoglycoside-type protein synthesis inhibitor being developed by Juvabis Therapeutics (Zurich, Switzerland) that recently started a phase-I trial evaluating IV dosing (NCT04105205). Apramycin (55) was discovered at Eli Lilly & Co (Indianapolis, IN, USA) in the 1960s [296] and its structure was published in 1976 [297] . Apramycin (55) is currently being used as veterinary antibiotic to treat E. coli infections [298] and it will be interesting to follow the impact of the possible re-purposing a veterinary drug into a human medicine and how this could impact its future animal use. Apramycin (55) has activity against carbapenem-and aminoglycoside-resistant Enterobacteriaceae, A. baumannii and P. aeruginosa [299] [300] [301] .

ACX-362E (56) is a bis-substituted guanine derivative [302, 303] that is being evaluated in a phase-I trial by Acurx Pharmaceuticals (White Plains, NY, USA) [304, 305] . ACX-362E (56) inhibits bacterial DNA polymerase IIIC and will be evaluated as potential treatment for CDI [306] . DNA polymerase IIIC, which is a new target for clinical development, is an essential enzyme in low guanine and cytosine classes of bacteria such as Bacillus, Clostridioides, Enterococcus, Mycoplasma, Lactobacillus, Listeria, Pneumococcus, Staphylococcus and Streptococcus. The discovery of ACX-362E (56) and a historical overview of the development of DNA polymerase IIIC inhibitors has recently been reviewed [305] .

Fluorothyazinone (57) (C-55, fluorothyazinon) recently completed a phase-I trial (NCT03205462), which was sponsored by Gamaleya Research Institute of Epidemiology and Microbiology, Health Ministry of the Russian Federation (Moscow, Russia). Fluorothyazinone (57) is an orally administered inhibitor the bacterial type III secretion system (T3SS) [307] [308] [309] , which is highly conserved in many G−ve pathogens that is considered to be a promising antivirulence target [310] . It will be interesting to follow the clinical development and later stage clinical trial design of this antivirulence agent. SPR720 (58) (pVXc-486) is a prodrug of the DNA gyrase inhibitor SPR719 (59) (VXc-486) that is being evaluated in a phase-I trial by Spero Therapeutics (Cambridge, MA, USA) as a potential oral treatment for TB and nontuberculous Mycobacterium (NTM) infections such as Mycobacterium avium complex and M. abscessus (NCT03796910) [311] [312] [313] [314] . SPR720 (58) inhibits DNA synthesis via DNA gyrase GyrB and Topoisomerase IV parC, which is similar to novobiocin [315] . The development of SPR720 (58) is being supported by the Novo REPAIR Fund (Copenhagen, Denmark) and the Bill & Melinda Gates Medical Research Institute (Cambridge, MA, USA), who fund the TB development [316] . SPR720 (58) and SPR719 (59) were discovered by Vertex Pharmaceuticals (Boston, MA, USA) [311, 312] . TXA709 (60) is an orally bioavailable prodrug of TXA707 (61) that belongs to the new FtsZ benzamide class, which inhibits an essential enzyme FtsZ (bacterial homolog of tubulin) in bacterial cell wall division in both G+ve and G−ve bacteria [317, 318] . TXA709 (60) is currently being evaluated in a phase-I trial by TAXIS Pharmaceuticals (Monmouth Junction, NJ, USA) [319] . The benzamide class, as exemplified by PC190723 [320] [321] [322] that has a Cl in place of the CF 3 in TXA707 (61), was discovered by Prolysis Ltd (Oxford, UK). Prolysis were bought in November 2009 by Biota Holdings (Melbourne, Australia) and Biota's FtsZ IP portfolio was licensed to TAXIS in August 2014 [323] . The development of PC190723 and its prodrug TXY541 [324] was hindered by poor physicochemical and PK properties; however, TXA709 (60) has enhanced metabolic stability, PK properties and superior in vivo efficacy against S. aureus compared with TXY541 [325, 326] .

BTZ-043 (48), which is a member of the anti-TB BTZ class, has recently completed a phase-I trial (NCT03590600). This trial was sponsored by the University of Munich (Munich, Germany), Hans-Knöll Institute (Jena, Germany) and the German Center for Infection Research (DZIF) (Heidelberg, Germany). As with macozinone (47), BTZ-043 (48) inhibits the essential mycobacterial cell wall biosynthesis enzyme DprE1 [269, 273, 276] .

TBI-223 (62) is an oxazolidinone being developed by the TB Alliance (New York, NY, USA) and the Institute of Materia Medica (Shanghai, People's Republic of China) that is currently being evaluated in a phase-I trial using oral dosing (NCT03758612). TBI-223 (62) has similar in vitro TB activity and in vivo properties in mouse models but has a higher safety margin in pre-clinical studies and enhanced metabolic properties compared to linezolid [327, 328] .

TBI-166 (63) (pyrifazimine) is an orally bioavailable clofazimine (64) analog [329] (riminophenazine class) that is being evaluated in a phase-I trial (ChiCTR1800018780) as a treatment for TB by the Global Alliance for TB Drug Development (64) has been used to treat leprosy since 1962 and has more recently been incorporated into short-course MDR-TB regimens [330, 331] ; however, clofazimine (64) has suboptimal PK/PD that leads to tissue accumulation, which due to its red color causes skin discoloration that can take months to clear. TBI-166 (63) was designed to have improved PK/PD properties, while maintaining potent anti-TB activity with less skin discoloration [332, 333] .

TBA-7371 (65) is a 1,4-azaindole that is being developed by the Global Alliance for TB Drug Development (New York, NY, USA), which has completed a phase-I trial (NCT03199339) that evaluated safety, tolerability, PK, and PK interactions using oral dosing. TBA-7371 (65) is a noncovalent DprE1 inhibitor that was discovered by researchers at AstraZeneca's Bangalore site in India by scaffold hopping from telacebec (46), which has a different mechanism [334] [335] [336] .

TNP-2198 (structure not disclosed but likely to be hybrid like TNP-2092 (36)) is being developed by TenNor Therapeutics (Suzhou, People's Republic of China) for diseases of anaerobic infections, which includes gastrointestinal diseases associated with H. pylori, bacterial vaginosis and CDAD [337] . TNP-2198 is being evaluated in a phase-I trial examining an ascending dose regimen and the effect of eating (CTR20190734).

BCM-0184 (structure not disclosed) is currently being evaluated by Biocidium Biopharmaceuticals (North Vancouver, BC, Canada) in a phase-I trial [338] . BCM-0184 has activity against MRSA and has oral and topical formulations, but no further information is available. DSTA4637S (66) (RG7861, Sym009) is an IV administered thiomab-type S. aureus mAb-rifamycin ADC [339, 340] being developed by Genentech (South San Francisco, CA, USA) that has successfully completed a phase-1 trial in healthy volunteers (NCT02596399) [341] and is currently being evaluated in a phase-I trial in patients with S. aureus bacteremia that are receiving antibacterials (NCT03162250). DSTA4637S (66) is designed to cleave in phagocytic cells, which can be a reservoir for S. aureus infections, and being developed for the treatment of serious S. aureus infections including MRSA. DSTA4637S (66) has an engineered human immunoglobulin G1 (IgG1) anti-S. aureus mAb (MSTA3852A) that was discovered in collaboration with Symphogen (Ballerup, Denmark), which binds to teichoic acid β-O-linked N-acetylglucosamine sugars in the cell wall, attached via a protease-cleavable valine-citrulline linker to a rifamycin derivative (dmDNA31) with an average stoichiometry of two antibiotic units to one mAb [339, 340, 342, 343] . The rifamycin derivative dmDNA31 exerts is activity through inhibition of RNA synthesis.

The discovery of the first β-lactamase inhibitor clavulanic acid (67) [344] [345] [346] , which was isolated from Streptomyces clavuligerus, was an important breakthrough that rescued β-lactams antibacterial activity. Augmentin, which is combination of clavulanic acid (67) and amoxicillin, is still heavily used today after 38 years of being sold. There have been four new BLI combinations approved in the last five years (Table 1 (14)). In this section, new BLI combinations undergoing clinical evaluation are discussed (Table 5 , Figs. 11 and 12 ). β-lactam/BLI combinations in phase-III trials Enmetazobactam (AAI 101) (68) is a clavulanic acid (67)type BLI [347] [348] [349] with activity against extended spectrum β-lactamases (ESBLs) and some class A and D carbapenemases that is currently being evaluated by Allecra Therapeutics Gmbh (Weil am Rhein, Germany)/Allecra SAS (Saint Louis, France) in combination with cefepime (69) in a phase-III trial for cUTI using IV administration (NCT03687255) ( Table 5 , Fig. 11 ).

ETX2514SUL is an IV administered combination of the DBO-type BLI durlobactam (70) (ETX2514) [350] [351] [352] , which also has antibacterial activity, and clavulanic acid-type BLA inhibitor sulbactam (71) , which was first launched in 1986. ETX2514SUL is active against MDR Acinetobacter spp. [353, 354] and is being evaluated by Entasis Therapeutics (Waltham, MA, USA) is a phase-III trial as a treatment for infections caused by A. baumannii-calcoaceticus complex (NCT03894046). ETX2514SUL has also been evaluated in a phase-II trial for acute pyelonephritis and cUTI (NCT03445195).

The boronate-type BLI taniborbactam (72) (VNRX-5133) [355] and cefepime (69) , which is a fourth-generation cephalosporin first approved in 1994, are being evaluated by VenatoRx Pharmaceuticals (Malvern, PA, USA) in a phase-III trial (NCT03840148) as an IV treatment for cUTI and acute pyelonephritis. Taniborbactam (72) has activity against both serine-and metallo-β-lactamases, including ESBL, OXA, KPC, NDM and VIM enzymes, and it was recently shown by X-ray crystallography that 72 bound to NDM-1 though cyclization of its acylamino oxygen onto the boron of the bicyclic core [356] .

β-Lactam/BLI combinations in phase-I trials Nacubactam (73) (OP0595, FPI-1459, RG6080, RO7079901), which is a DBO-type BLI [357] [358] [359] , and meropenem (13) , which is a carbapenem first approved in 1998, was developed by Meiji Seika Pharma, Co. Ltd. (Tokyo, Japan) and Fedora Pharmaceuticals (Edmonton, AB, Canada). Meji and Fedora formed the joint venture NacuGen Therapeutics (Edmonton, AB, Canada) in January 2019 for further development of nacubactam (73) [360] . Meiji Seika and Fedora had previously partnered with Roche (Basel, Switzerland) [361, 362] and several phase-I trials using IV dosing have been completed (Meiji Seika: NCT02134834; Roche: NCT02972255, NCT02975388 and NCT03174795) ( Table 5 , Fig. 12) .

A DBO-type BLI, zidebactam (74) (WCK 5107), is being developed in combination with the fourth generation cephalosporin cefepime (69) (combination WCK 5222, FEP-ZID) by Wockhardt Limited (Mumbai, India) and has completed five phase-I trials using IV dosing (NCT02532140 [363] , NCT02674347, NCT02707107, NCT02942810, NCT03630094). Zidebactam (74) inhibits PBPs and several β-lactamases while enhancing β-lactam activity [364] and the combination shows in vitro and in vivo activity against G−ve bacteria such as A. baumannii, P. aeruginosa and CRE [364] [365] [366] [367] [368] .

ETX0282CPDP, which is a combination of the DBOtype BLI ETX0282 (75) and cefpodoxime proxetil (77), is currently being evaluated in a phase-I trial using oral dosing (NCT03491748) by Entasis Therapeutics (Waltham, MA, USA) with partial CARB-X (Boston, MA, USA) funding [369] . Both ETX0282 (75) and cefpodoxime proxetil (77) are prodrugs that are hydrolyzed in vivo releasing their active metabolites, ETX1317 (76) and cefpodoxime (78) [370, 371] . ETX0282 (75) is noteworthy as the N-oxysulfonic acid group previously found in DBO BLIs has been replaced with (R)-2-(N-oxy)-2-fluoroacetic acid; ETX0282 (75) also displays antibacterial activity against E. coli in addition to BLI activity.

A combination of the boronate-type BLI VNRX-7145 (79) [372, 373] and ceftibuten (80) , which is a third generation cephalosporin first approved in 1995, is currently being developed by VenatoRx Pharmaceuticals (Malvern, PA, USA) [374] . VNRX-7145 (79) has activity against CRE (KPC and OXA carbapenemases) and ESBLs. Both VNRX-7145 (79) and ceftibuten (80) are orally bioavailable, which is a differentiator to VenatoRx's more advanced IV administered, phase-III taniborbactam (72) and cefepime (69) program.

ARX-1796 (81) (ARX-006) is an orally bioavailable prodrug derivative of the approved DBO-type BLI avibactam (82) [375, 376] being developed by Arixa Pharmaceuticals (Palo Alto, CA, USA) that recently started a phase-I trial (NCT03931876).

Compounds and β-lactam/BLI combinations that have been discontinued from clinical development or have had their development halted since the 2015 review [2] are listed in Table 6 with comments about their the development halt or cessation noted if known.

Numbers of compounds undergoing clinical evaluation and their source derivation There are currently 44 compounds, eight β-lactam/BLI inhibitor combinations currently and one ADC undergoing clinical trials (Figs. 13 and 14) . Of the 44 compounds, two are in NDA/MAA (Table 2, Fig. 4) , eight are in phase-III (Table 2 ; Fig. 5 ), 18 in phase-II (Table 3 ; Figs. 6 and 7) and 16 in phase-I (Table 4 ; Figs. 8 and 9), three β-lactam/BLI combinations in phase-III (Table 5 ; Fig. 11 ) and five in phase-I (Table 5 ; Fig. 12 ) and one ADC in Phase-I (Table 4 , Fig. 10 ). Of the 44 compounds, 27 antibacterials were synthetically-derived (S), 14 were NP-derived (NP), one protein/mammalian peptide-derived (P), one ADC and the derivation of two are not known (Fig. 13 ).

There has been a similar number of compounds in the different development phases between 2011, 2013 and 2015, except for in phase-III trials in 2011 (6) compared with 2013 (16) and 2015 (15) . In 2019, the number in phase-III/NDA (13) and phase-II (18) is similar to previous years, but the number in phase-I trials (22) in 2019 has increased from an average 12 compounds in the previous reviews [1] [2] [3] . Thirteen of the phase-I compounds target G−ve bacteria (seven compounds including one antivirulence and five BLI combinations), while there are nine with G+ve activity (including five against TB and one for CDI). It will be interesting to monitor how many of the current phase-I antibacterials move to phase-II studies and beyond in the next few years and whether this higher number of antibacterials in phase-I level will be maintained or even increased.

The modes of action of nearly all antibacterial drugs can be categorized into four major "macro" level classes: cell wall, protein synthesis, DNA synthesis and RNA synthesis inhibitors [377] . In the TB field, there is also an emerging mode of action around the mycobacterial respiratory system, which is inhibited by bedaquiline (launched 2012) and the clinical candidate telacebec (46) [378] . Recent work has also shown that inhibition of the respiratory system in other bacteria is an important factor in bacteria cell death [379] . The "macro" mode of action classes (e.g., cell wall inhibitors) are further divided into structure classes (e.g., β-lactam), which and sometimes further into structure subclasses (e.g., penicillins, cephalosporins, carbapenems, and monobactams). A pharmacophore is the common sub-unit of active molecules that interacts with the biological target (e.g., the β-lactam subunit of the β-lactam antibacterials).

In this review, new pharmacophores not previously used in a human antibacterial drug have been analyzed as a measure of antibacterial structure innovation (Table 7) . There are 19 different compounds with six in phase-I, 9 in phase-II and 4 in phase-III (Fig. 15 ) and this is slightly higher than previous reviews: 11 in 2011, 17 in 2013 and 15 in 2015 (Fig. 16) . Fifteen of these compounds have new structure classes and/or new mode of action of the well-established "macro" targets: cell wall (9), DNA (5) and protein synthesis inhibition (1) . There are no new RNA synthesis inhibitors in clinical development. There are no new BLI classes in development after the recent approvals of the DBO (avibactam, 2015) and boronate classes (vaborbactam, (12) , 2017). The ADC DSTA4637S (66) was not classified as a new pharmacophore as the payload is a rifamycin derivative; however, if approved, it would be a first antibacterial ADC alongside and would add to the three approved mAbs, raxibacumab, obiltoxaximab, and bezlotoxumab (Table 1) .

Existing antibacterial classes that inhibit the bacterial cell wall include the β-lactams, glycopeptides, fosfomycin, cylcloserine; daptomycin (lipopeptide) and polymyxin. The new cell wall antibacterials inhibit several different targets (LptD: murepavadin (22) , FabI: afabicin (40), 3 × DprE: macozinone (47)/BTZ-043 (48), OPC-167832 (49), and TBA-7371 (65), and FtsZ: TXA709 (60)) and two that have less defined mechanisms (ridinilazole (24) and XF-73 (35)) ( Table 7) .

There is currently one class of DNA synthesis inhibitors (DNA gyrase GyrA and Topoisomerase IV parC), the quinolones, in clinical use. Novobiocin has not been clinically used for many years but it inhibits DNA gyrase GyrB and Topoisomerase IV parE [313, 315] . SPR720 (58) is an "ethyl urea benzimidazole" that also inhibits GyrB and parE, while geptotidacin (25) inhibits GyrB at a different site to the quinolones and zoliflodacin (26) inhibits GyrB [315] . The dichlorobenyl guanine ACX-362E (56) inhibits a new target DNA polymerase IIIC. MGB-BP-03 (34) belongs to the distamycin class that is a DNA groove binder, which is the mechanism also found in several anticancer drugs, such as daunorubicin, dactinomycin, and bleomycins.

The protein synthesis inhibitor class has many representatives that include the macrolides, aminoglycosides, tetracyclines, lincosamides, chloramphenicol, oxazolidinones, pleuromutilins, and streptogramins. Other protein synthesis inhibitors include fusidic acid, which inhibits elongation factor G, and mupirocin that inhibits isoleucine t-RNA synthetase (IleRS). The oxaborole GSK656 (50) is a new pharmacophore that inhibits leucine t-RNA synthetase (LeuRS), which would be a new antibacterial mechanism.

Telacebec (46) and bedaquiline both have inhibitory effects on the bacterial electron-transport chain (respiration). Auranofin (38) targets thiol-redox homeostasis through thioredoxin reductase inhibition, while niclosamide (39) inhibits oxidative phosphorylation (amongst other mechanisms) but also has been reported to inhibit quorum sensing in P. aeruginosa. Fluorothyazinone (57) inhibits the G−ve type III secretion system, which is an antivirulence target that has not been previously explored in the clinic.

The antibacterial clinical pipeline's administration routes (po, oral; iv/po intravenous oral switch; iv, intravenous; po topical, CDI oral; topical, topical or drops) was analyzed by development phase (Fig. S1 ) and lead source (Fig. S2) . Oral administration is the most predominate route (27) with just under 50% (13) being 13 TB clinical candidates, for which oral administration route is almost mandatory. The second highest category is iv administration with 17, while there are six candidates that use iv/po; the iv/po switch strategy is used when patients move from iv administration in intensive care to oral afterwards. Eight of the 15 iv administered drugs are derived from NP lead, which is not unexpected due their physico-chemical properties [21, 380] . The po topical (5) administration route is used to treat for gastrointestinal infections, such as C. difficile and H. pylori. For po topical, the clinical candidates are taken orally as tablets, but are not significantly systemically absorbed; this contrasts with po administered compounds that are taken orally but pass through the gut and into blood for delivery throughout the body. Interestingly, one of the CDI clinical candidates, DNV-3837 (44) is being developed using iv administration, which differentiates it to the other five CDI clinical candidates in development and marketed drugs that use the po topical route. Finally, there are three topical delivered candidates that can be delivered as creams and eye drops.

The antibacterial pipeline composition (number, phase breakdown, and pharmacophores) is similar previous numbers in 2011 [3] , 2013 [2] , and 2015 [1] except for a spike in the number of phase-I candidates from 11 in 2015 to 21 in 2019 (Fig. 14) . It is likely that this increase in phase-I candidates has been helped by increased funding and the development expertise offered by organizations like the Wellcome Trust (London, UK), BARDA (Washington DC, USA), GARDP (Geneva, Switzerland), CARB-X (Boston, MA, USA) and the Novo Holdings's REPAIR Impact Fund (Copenhagen, Denmark), as well as funding provided for the development of new anti-Mycobacterium drugs by organizations such as the TB Alliance (New York, NY, USA) and Bill & Melinda Gates Foundation (Seattle, WA, USA). However, despite this increase, there are also some unmet medical needs that need to be addressed in the clinical pipeline: new antibacterials with activity against β-metallolactamases, orally administered that have broad spectrum G−ve activity, and new treatments for MDR Acinetobacter and gonorrhea. It is imperative that we discover and develop new antibacterials, especially against these unmet medical needs, to keep replenishing the pipeline and help limit the health impacts of MDR bacteria. 

Antibiotics in the clinical pipeline at the end of 2015

Antibiotics in the clinical pipeline in 2013

Antibiotics in the clinical pipeline in 2011

Karlén A The global preclinical antibacterial pipeline

Analysis of the clinical antibacterial and antituberculosis pipeline

Progress in the fight against multidrug-resistant bacteria? A review of U.S. Food and Drug Administration-approved antibiotics

Antibiotics in late clinical development

Infections by multidrug-resistant Gram-negative bacteria: What's new in our arsenal and what's in the pipeline?

Antibacterials in the pipeline and perspectives for the near future

Antibiotic discovery: where have we come from, where do we go? Antibiotics (Basel)

The small-molecule antibiotics pipeline

Natural products as platforms to overcome antibiotic resistance

Thinking outside the box-novel antibacterials to tackle the resistance crisis

Revitalizing the drug pipeline: antibiotic DB, an open access database to aid antibacterial research and development

Antibacterial drug discovery: some assembly required

Discovery and development of new antibacterial drugs: learning from experience?

Future antibacterial strategies: from basic concepts to clinical challenges

Meeting the discovery challenge of drug-resistant infections: progress and focusing resources

Technologies to address antimicrobial resistance

Perspective on antibacterial lead identification challenges and the role of hypothesis-driven strategies

Size matters and how you measure it: a gram-negative antibacterial example exceeding typical molecular weight limits

Inter)nationalising the antibiotic research and development pipeline

Alternatives to antibiotics-a pipeline portfolio review

Non-traditional antibacterial therapeutic options and challenges

Phage therapy: current status and perspectives

β-Lactam/β-lactamase inhibitor combinations: an update

β-Lactamases and β-lactamase inhibitors in the 21st century

Signed, sealed, delivered: conjugate and prodrug strategies as targeted delivery vectors for antibiotics

Antimicrobial resistance: the complex challenge of measurement to inform policy and the public

Garrod Lecture: preparing for the Black Swans of resistance

Engel A The broken antibiotics business model Part I

Engel A The broken antibiotics business model Part II

Engel A The broken antibiotics business model Part III

Engel A The broken antibiotics business model Part IV

International Society of Antimicrobial Chemotherapy new drugs for multidrug-resistant Gram-negative organisms: Time for stewardship

Complexities in understanding antimicrobial resistance across domesticated animal, human, and environmental systems

Challenges in antibiotic R&D calling for a global strategy considering both short-and long-term solutions

Investing in antibiotics to alleviate future catastrophic Streptococcus pneumoniae

In vitro and in vivo antibacterial activities of DW-224a, a new fluoronaphthyridone

Zabofloxacin (DW-224a) activity against Neisseria gonorrhoeae including quinolone-resistant strains

Dong Wha Pharm's quinolone antibacterial agent

Delafloxacin: a new anti-methicillinresistant Staphylococcus aureus fluoroquinolone

Efficacy and safety of delafloxacin in the treatment of acute bacterial skin and skin structure infections: a systematic review and metaanalysis of randomized controlled trials

Melinta Therapeutics Launches Antibiotic Baxdela™ (delafloxacin) in the United States

Delafloxacin: a novel fluoroquinolone with activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa

FDA approval of supplemental new drug application for BAXDELA® (delafloxacin) for the treatment of community-acquired bacterial pneumonia (CABP) (Press Release

Synthesis and spectrum of the neoglycoside ACHN-490

Teaching an old class new tricks: a novel semi-synthetic aminoglycoside, plazomicin

Plazomicin: a novel aminoglycoside for the treatment of resistant Gram-negative bacterial infections

Antibiotic 6640, a new Micromonospora-produced aminoglycoside antibiotic

Structure of sisomicin, a novel unsaturated aminocyclitol antibiotic from Micromonospora inyoensis

UPDATE -ZEMDRI™ (plazomicin) approved by FDA for the treatment of adults with complicated urinary tract infections (cUTI) (Press Release 26

Achaogen submits Marketing Authorization Application to the European Medicines Agency for plazomicin

Achaogen plans for near-term sale using structured process through Chapter 11 of the U.S. Bankruptcy Code (Press Release 15

announces results of auction for substantially all company assets (Press Release 6

1. 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: a potent, broad spectrum antibacterial agent

Fluorocyclines. 2. Optimization of the C-9 side-chain for antibacterial activity and oral efficacy

Eravacycline, a newly approved fluorocycline

Tetraphase Pharmaceuticals receives positive CHMP opinion for Xerava™ (eravacycline) as a treatment for complicated intraabdominal infections

Tetraphase Pharmaceuticals announces commercial launch of Zerava™ in the United States (Press Release

IGNITE4: Results of a phase 3, randomized, multicenter, prospective trial of eravacycline vs. meropenem in the treatment of complicated intra-abdominal infections

Tetraphase announces top-line results from IGNITE3 phase 3 clinical trial of eravacycline in complicated urinary tract infections (cUTI) (Press Release 13

Omadacycline: a novel tetracycline derivative with oral and intravenous formulations

Paratek announces FDA approval of NUZYRA™ (Omadacycline)

Omadacycline: first global approval

Once-daily oral omadacycline versus twice-daily oral linezolid for acute bacterial skin and skin structure infections (OASIS-2): a phase 3, double-blind, multicentre, randomised, controlled, non-inferiority trial

Paratek withdraws European Marketing Authorization application for oral and intravenous NUZYRA in skin infections and pneumonia (Press release

Sarecycline: first global approval

Sarecycline: a narrow spectrum tetracycline for the treatment of moderate-to-severe acne vulgaris

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Once-daily oral sarecycline 1.5 mg/kg/day is effective for moderate to severe acne vulgaris: results from two identically designed, phase 3, randomized, double-blind clinical trials

A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis

FDA approves new treatment for highly drug-resistant forms of tuberculosis

PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release

The mechanism of action of PA-824: novel insights from transcriptional profiling

Mutations in genes for the F420 biosynthetic pathway and a nitroreductase enzyme are the primary resistance determinants in spontaneous in vitro-selected PA-824-resistant mutants of Mycobacterium tuberculosis

Untargeted metabolomics reveals a new mode of action of pretomanid (PA-824)

Are pleuromutilin antibiotics finally fit for human use?

The pleuromutilin antibiotics: a new class for human use

Lefamulin: Review of a promising novel pleuromutilin antibiotic

FDA approves new antibiotic to treat community-acquired bacterial pneumonia

EMA) validation of marketing authorization application for lefamulin (Press Release

Antimicrobial activity of the investigational pleuromutilin compound BC-3781 tested against Gram-positive organisms commonly associated with acute bacterial skin and skin structure infections

Antimicrobial activity of the novel pleuromutilin antibiotic BC-3781 against organisms responsible for community-acquired respiratory tract infections (CARTIs)

In vitro activity of lefamulin tested against Streptococcus pneumoniae with defined serotypes, including multidrug-resistant isolates causing lower respiratory tract infections in the United States

In vitro activity of lefamulin against sexually transmitted bacterial pathogens

vitro activities and spectrum of the novel fluoroquinolone lascufloxacin (KRP-AM1977)

In vitro activity of lascufloxacin, a novel fluoroquinolone antibacterial agent, against various clinical isolates of anaerobes and Streptococcus anginosus group

Kyorin Pharmaceutical receives marketing approval for oral quinolone antibacterial agent

S-649266), a new siderophore cephalosporin exhibiting potent activities against Pseudomonas aeruginosa and other Gram-negative pathogens including multi-drug resistant bacteria: structure activity relationship

Cefiderocol: a novel siderophore cephalosporin

In vitro antimicrobial activity of siderophore cephalosporin S-649266 against Enterobacteriaceae clinical isolates including carbapenem-resistant strains

In vitro activity of cefiderocol, a siderophore cephalosporin, against Gram-negative bacilli isolated by clinical laboratories in North America and Europe in 2015-2016: SIDERO-WT-2015

FETROJA® (cefiderocol) approved by the FDA for treatment of complicated urinary tract infections (cUTI) in adult patients with limited or no alternative treatment options (Press Release

Cefiderocol versus imipenemcilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial

The Medicines Company announces FDA approval of VABO-MERE™ (meropenem and vaborbactam) (Press Release

Imipenem-relebactam and meropenem-vaborbactam: two novel carbapenem-β-lactamase inhibitor combinations

The Medicines Company announces definitive agreement to sell its infectious disease business unit to Melinta Therapeutics

Melinta Therapeutics granted European Commission Marketing Authorization for Vabomere ® (meropenem and vaborbactam) (Press Release

inventors; Rempex Pharmaceuticals, Inc., assignee. Cyclic boronic acid ester derivatives and therapeutic uses thereof

FDA approves new treatment for complicated urinary tract and complicated intra-abdominal infections

Prospective, randomized, double-blind, Phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections

Phase 2, dose-ranging study of relebactam with imipenem-cilastatin in subjects with complicated intra-abdominal infection

A concise synthesis of a β-lactamase inhibitor

Two decades of imipenem therapy

Spotlight on solithromycin in the treatment of community-acquired bacterial pneumonia: design, development, and potential place in therapy

Application for manufacturing and sales approval in Japan filed for T-4288, an antibacterial agent

Cempra receives Complete Response Letter from FDA for Solithromycin NDAs

Cempra withdraws solithromycin Marketing Authorization Application in Europe

Increased hydrophobic interactions of iclaprim with Staphylococcus aureus dihydrofolate reductase are responsible for the increase in affinity and antibacterial activity

An updated review of iclaprim: a potent and rapidly bactericidal antibiotic for the treatment of skin and skin structure infections and nosocomial pneumonia caused by Grampositive including multidrug-resistant bacteria

EMEA. Questions and answers on the withdrawal of the marketing authorisation application for Mersarex (iclaprim

Motif Bio submits NDA for iclaprim (Press Release 14

Motif Bio confirms meeting date with U.S. FDA regarding iclaprim

In vitro antibacterial activity and β-lactamase stability of CP-70,429 a new penem antibiotic

Pharmacokinetics of the penem CP-65,207 and its separate stereoisomers in humans

Development of a practical and convergent process for the preparation of sulopenem

Development of a second-generation process to antibacterial candidate sulopenem

Iterum announces sulopenem in development for treatment of Gram-negative, multi-drug resistant infections (Press Release 5

A phase 1 study to assess the pharmacokinetics of sulopenem etzadroxil (PF-03709270)

Once-daily cefazolin and probenecid for skin and soft tissue infections

Peptidomimetic antibiotics target outermembrane biogenesis in Pseudomonas aeruginosa

Protein epitope mimetics: from new antibiotics to supramolecular synthetic vaccines

Murepavadin: a new antibiotic class in the pipeline

A peptidomimetic antibiotic interacts with the periplasmic domain of LptD from Pseudomonas aeruginosa

Insertion of proteins and lipopolysaccharide into the bacterial outer membrane

Polyphor temporarily halts enrollment in the phase III studies of murepavadin for the treatment of patients with nosocomial pneumonia (Press Release 9

Polyphor closes the phase III PRISM studies of murepavadin intravenous formulation and evaluates further product improvement options (Press Release

Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates

Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action

Infectex announces positive phase 2b-3 clinical trial results of SQ109 for the treatment of multidrug-resistant pulmonary tuberculosis

Efficiency and safety of chemotherapy regimen with SQ109 in those suffering from multiple drug resistant tuberculosis

High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial

The embAB genes of Mycobacterium avium encode an arabinosyl transferase involved in cell wall arabinan biosynthesis that is the target for the antimycobacterial drug ethambutol

Novel insights into the pharmacometabonomics of first-line tuberculosis drugs relating to metabolism, mechanism of action and drug-resistance

Molecular mechanism of the synergistic activity of ethambutol and isoniazid against Mycobacterium tuberculosis

Ethambutol targets the glutamate racemase of Mycobacterium tuberculosis-an enzyme involved in peptidoglycan biosynthesis

Novel insights into the mechanism of inhibition of MmpL3, a target of multiple pharmacophores in Mycobacterium tuberculosis

Multitarget drug discovery for tuberculosis and other infectious diseases

SQ109, a new drug lead for Chagas disease

Ridinilazole: a novel therapy for Clostridium difficile infection

Summit announces BARDA increases award for ridinilazole clinical and regulatory development to up to $63.7 million and exercises next contract option (Press Release 18

Impact on toxin production and cell morphology in Clostridium difficile by ridinilazole (SMT19969), a novel treatment for C. difficile infection

Enhanced preservation of the human intestinal microbiota by ridinilazole, a novel Clostridium difficile-targeting antibacterial, compared to vancomycin

Mechanistic and structural basis for the actions of the antibacterial gepotidacin against Staphylococcus aureus gyrase

Microbiological analysis from a phase 2 randomized study in adults evaluating single oral doses of gepotidacin in the treatment of uncomplicated urogenital gonorrhea caused by Neisseria gonorrhoeae

Gepotidacin for the treatment of uncomplicated urogenital gonorrhea: a phase 2, randomized, dose-ranging, single-oral dose evaluation

Gepotidacin (GSK2140944) in vitro activity against Gram-positive and Gram-negative bacteria

Analysis of MIC and disk diffusion testing variables for gepotidacin and comparator agents against select bacterial pathogens

In vitro activity of gepotidacin, a novel triazaacenaphthylene bacterial topoisomerase inhibitor, against a broad spectrum of bacterial pathogens

In vitro activity of the novel triazaacenaphthylene gepotidacin (GSK2140944) against MDR Neisseria gonorrhoeae

In vitro activities of gepotidacin (GSK2140944) and other antimicrobial agents against Human mycoplasmas and ureaplasmas

Inhibition of Neisseria gonorrhoeae type II topoisomerases by the novel spiropyrimidinetrione AZD0914

High in vitro activity of the novel spiropyrimidinetrione AZD0914, a DNA gyrase inhibitor, against multidrug-resistant Neisseria gonorrhoeae isolates suggests a new effective option for oral treatment of gonorrhea

In vitro activity of zoliflodacin (ETX0914) against macrolide-resistant, fluoroquinolone-resistant and antimicrobial-susceptible Mycoplasma genitalium strains

Single-dose zoliflodacin (ETX0914) for treatment of urogenital gonorrhea

New potent antibacterial oxazolidinone (MRX-I) with an improved class safety profile

MicuRx reports positive top-line results of a China phase 3 clinical trial for novel antibiotic contezolid in complicated skin and soft tissue infections

Selection and characterisation of Staphylococcus aureus mutants with reduced susceptibility to the investigational oxazolidinone MRX-I

In vivo antibacterial activity of MRX-I, a new oxazolidinone

In vitro and in vivo activities of contezolid (MRX-I) against Mycobacterium tuberculosis

inventors; MicuRx Pharmaceuticals, assignee. Water-soluble O-carbonyl phosphoramidate prodrugs for therapeutic administration. United States patent US 9

Intrapulmonary pharmacokinetics of levonadifloxacin following oral administration of alalevonadifloxacin to healthy adult subjects

Identification of metabolites of novel Anti-MRSA fluoroquinolone WCK 771 in mouse, rat, rabbit, dog, monkey and human urine using liquid chromatography tandem mass spectrometry

Nadifloxacin: A quinolone for topical treatment of skin infections and potential for systemic use of its active isomer, WCK 771

In vitro activity of the quinolone WCK 771 against recent U.S. hospital and community-acquired Staphylococcus aureus pathogens with various resistance types. Antimicrob Agents Chemother

A chiral benzoquinolizine-2-carboxylic acid arginine salt active against vancomycin-resistant Staphylococcus aureus

In vitro activity of LYS228, a novel monobactam antibiotic, against multidrug-resistant Enterobacteriaceae

Optimization of novel monobactams with activity against carbapenem-resistant Enterobacteriaceae-identification of LYS228

Mode of action of the monobactam LYS228 and mechanisms decreasing in vitro susceptibility in Escherichia coli and Klebsiella pneumoniae

A first-in-Human study to assess the safety and pharmacokinetics of LYS228, a novel intravenous monobactam antibiotic in healthy volunteers

Novartis licenses three novel anti-infective programs to Boston Pharmaceuticals

Sihuan Pharmaceutical Holdings Group Ltd

A first-in-human safety, tolerability, and pharmacokinetics study of benapenem in healthy Chinese volunteers

Comparison of plasma and intrapulmonary concentrations of nafithromycin (WCK 4873) in healthy adult subjects

Determination of disk diffusion and MIC quality control ranges for nafithromycin (WCK 4873), a new lactone-ketolide

Antimicrobial lexitropsins containing amide, amidine, and alkene linking groups

Photodynamic effects of novel XF porphyrin derivatives on prokaryotic and eukaryotic cells

XF-73, a novel antistaphylococcal membrane-active agent with rapid bactericidal activity

In vitro activity of XF-73, a novel antibacterial agent, against antibioticsensitive and -resistant Gram-positive and Gram-negative bacterial species

XF-70 and XF-73, novel antibacterial agents active against slowgrowing and non-dividing cultures of Staphylococcus aureus including biofilms

A two-part phase I study to establish and compare the safety and local tolerability of two nasal formulations of XF-73 for decolonization of Staphylococcus aureus: a previously investigated 0.5 mg/g viscosified gel formulation versus a modified formulation

TenNor receives QIDP designation for TNP-2092

Development of a dual-acting antibacterial agent (TNP-2092) for the treatment of persistent bacterial infections

In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: microbiology profiling studies with staphylococci and streptococci

In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: studies of the mode of action in Staphylococcus aureus

Antibacterial use of halogenated salicylanilides

Dosage regimen of halogenated salicylanilides World patent WO

The biology and toxicology of molluscicides

UNION Therapeutics announces completion of phase 2 studies with ATx201

Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus

Repurposing niclosamide for intestinal decolonization of vancomycin-resistant enterococci

The anthelmintic drug niclosamide synergizes with colistin and reverses colistin resistance in Gram-negative bacilli

Beyond an antihelminthic drug

Niclosamide, a drug with many (re)purposes. ChemMedChem

Nitazoxanide disrupts membrane potential and intrabacterial pH homeostasis of Mycobacterium tuberculosis

New life for an old drug: The anthelmintic drug niclosamide inhibits Pseudomonas aeruginosa quorum sensing

Oral gold. Antiarthritic properties of alkylphosphinegold coordination complexes

Mechanism of action, pharmacology, clinical efficacy and side effects of auranofin: An orally administered organic gold compound for the treatment of rheumatoid arthritis

Auranofin: Repurposing an old drug for a golden new age

Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis

Mycobacterium tuberculosis thioredoxin reductase is essential for thiol redox homeostasis but plays a minor role in antioxidant defense

Repurposing of auranofin: Thioredoxin reductase remains a primary target of the drug

Antibacterial activity and mechanism of action of auranofin against multi-drug resistant bacterial pathogens

Auranofin disrupts selenium metabolism in Clostridium difficile by forming a stable Au-Se adduct

Repurposing auranofin as an intestinal decolonizing agent for vancomycin-resistant enterococci

Repurposing auranofin as a Clostridioides difficile therapeutic

Auranofin and N-heterocyclic carbene goldanalogs are potent inhibitors of the bacteria Helicobacter pylori

Auranofin efficacy against MDR Streptococcus pneumoniae and Staphylococcus aureus infections

Synergistic microbicidal effect of auranofin and antibiotics against planktonic and biofilm-encased S. aureus and E. faecalis. Front Microbiol

In vitro efficacy of bismuth thiols against biofilms formed by bacteria isolated from human chronic wounds

Microbion Corporation, assignee. Bismuth-thiols as antiseptics for agricultural, industrial and other uses. Unites States patent US 9

Microbion and Haisco announce equity investment and development & commercialization agreement for MBN-101 in China and Related Territories

Bismuth subsalicylate: History, chemistry, and safety

The antimicrobial spectrum of Xeroform ®

Role of bismuth in the eradication of Helicobacter pylori

Bone and joint tissue penetration of the Staphylococcus-selective antibiotic afabicin in patients undergoing elective hip replacement surgery

Perturbation of Staphylococcus aureus gene expression by the enoyl-acyl carrier protein reductase inhibitor AFN-1252

Mode of action, in vitro activity, and in vivo efficacy of AFN-1252, a selective antistaphylococcal FabI inhibitor

Inhibitors of FabI, an enzyme drug target in the bacterial fatty acid biosynthesis pathway

Recent advances in the inhibition of bacterial fatty acid biosynthesis

Discovery of a novel and potent class of FabI-directed antibacterial agents

Drugs for bad bugs: confronting the challenges of antibacterial discovery

Efficacy and safety of AFN-1252, the first Staphylococcus-specific antibacterial agent, in the treatment of acute bacterial skin and skin structure infections, including those in patients with significant comorbidities

In vitro and in vivo activities of LCB01-0371, a new oxazolidinone

Comparison of in vitro activity and MIC distributions between the novel oxazolidinone delpazolid and linezolid against multidrugresistant and extensively drug-resistant Mycobacterium tuberculosis in China

Activity of LCB01-0371, a novel oxazolidinone, against Mycobacterium abscessus

HaiHe Biopharma and CSPC formed a joint venture to codevelop innovative drugs (Press release 18

Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity

Activities of several novel oxazolidinones against Mycobacterium tuberculosis in a murine model

Susceptibility of cinical Mycobacterium tuberculosis isolates to a potentially less toxic derivate of linezolid, PNU-100480. Antimicrob Agents Chemother

Promising antituberculosis activity of the oxazolidinone PNU-100480 relative to that of linezolid in a murine model

Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis

DEINOVE is now ready to start Phase II clinical trial for its antibiotic compound DNV3837

In vitro activity of MCB3681 against Clostridium difficile strains

Ecological impact of MCB3837 on the normal human microbiota

Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle

DNV3837: An antibiotic in the clinical phase to fight severe Clostridioides difficile infections and DNV3681 evaluated by the U.S. Department of Defense as a potential treatment against two pathogenic agents classified as most dangerous possible bioterrorist threat

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

Lead optimization of a novel series of imidazo[1,2-a]pyridine amides leading to a clinical candidate (Q203) as a multi-and extensively-drug-resistant anti-tuberculosis agent

Arrival of imidazo[2,1-b]thiazole-5-carboxamides: Potent anti-tuberculosis agents that target QcrB

Inhibitors of energy metabolism interfere with antibiotic-induced death in mycobacteria

Infectex successfully completes phase 1 clinical study of Q203 for treatment of tuberculosis (Press release

Towards a new combination therapy for tuberculosis with next generation benzothiazinones

Spirocyclic and bicyclic 8-nitrobenzothiazinones for tuberculosis with improved physicochemical and pharmacokinetic properties

Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis

Benzothiazinones are suicide inhibitors of mycobacterial decaprenylphosphoryl-β-D-ribofuranose 2′-oxidase DprE1

Structural basis for benzothiazinone-mediated killing of Mycobacterium tuberculosis

In vitro activity of PBTZ169 against multiple Mycobacterium species. Antimicrob Agents Chemother

In vivo dearomatization of the potent antituberculosis agent BTZ043 via Meisenheimer complex formation

OPC-167832 (Working Group on New TB Drugs

inventors; Otsuka Pharmaceutical, assignee. Heterobicyclic compounds and their use for the treatment of tuberculosis

Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors

Discovery of a potent and specific M. tuberculosis leucyl-tRNA synthetase inhibitor: (S)-3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol (GSK656)

First-time-in-Human study and prediction of early bactericidal activity for GSK3036656, a potent leucyl-tRNA synthetase inhibitor for tuberculosis treatment. Antimicrob Agents Chemother

Discovery of novel oral protein synthesis inhibitors of Mycobacterium tuberculosis that target leucyl-tRNA synthetase

Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections. Antimicrob Agents Chemother

A polymorphism in leuS confers reduced susceptibility to GSK2251052 in a clinical isolate of Staphylococcus aureus

Activity of TP-6076 against carbapenem-resistant Acinetobacter baumannii isolates collected from inpatients in Greek hospitals

TP-6076 selected by Carb-X to receive $4 million in research funding (Press Release

Fluorocycline TP-271 is potent against complicated community-acquired bacterial pneumonia pathogens

The fluorocycline TP-271 is efficacious in models of aerosolized Francisella tularensis SCHU S4 infection in BALB/c mice and cynomolgus macaques

The fluorocycline TP-271 is efficacious in models of aerosolized Bacillus anthracis infection in BALB/c mice and cynomolgus macaques

Polymyxin: Alternative mechanisms of action and resistance

Polymyxin derivatives that sensitize Gram-negative bacteria to other antibiotics

Structure-activity studies on novel polymyxin derivatives that carry only three positive charges. Peptides

A novel polymyxin derivative that lacks the fatty acid tail and carries only three positive charges has strong synergism with agents excluded by the intact outer membrane

Potentiation of antibiotic activity by a novel cationic peptide: Potency and spectrum of activity of SPR741

SPR741, an antibiotic adjuvant, potentiates the in vitro and in vivo activity of rifampin against clinically relevant extensively drug-resistant Acinetobacter baumannii

Assessment of the in vivo activity of SPR741 in combination with azithromycin against multidrug-resistant Enterobacteriaceae isolates in the neutropenic murine thigh infection model

SPR206, against non-fermentative Gram-negative bacilli responsible for human infections (ASM-ESCMID Conference

Spero Therapeutics signs license agreement with Everest Medicines to develop, manufacture and commercialize SPR206 in Asia, with option for SPR741 rights, and initiates SPR206 Phase 1

a new broad-spectrum antibiotic complex. III. Isolation and chemical-physical properties

Apramycin, a unique aminocyclitol antibiotic

Tentative epidemiologic cut-off value and resistant characteristic detection of apramycin against Escherichia coli from chickens

In vitro apramycin activity against multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa

In vitro activity of apramycin against multidrug-, carbapenem-and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii

Efficacy of apramycin against multidrug-resistant Acinetobacter baumannii in the murine neutropenic thigh model

Active site directed inhibitors of replicationspecific bacterial DNA polymerases

7-Alkyl-N2-substituted-3-deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity

Acurx announces first-in-man clinical trial data of ACX-362E for CDI

Discovery and development of DNA polymerase IIIC inhibitors to treat Gram-positive infections

A novel agent effective against Clostridium difficile infection

A small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones suppresses Salmonella infection in vivo

Development of chlamydial type III secretion system inhibitors for suppression of acute and chronic forms of chlamydial infection

Small molecule inhibitor of type three secretion system belonging to a class 2,4-disubstituted-4H-[1,3,4]-thiadiazine-5-ones improves survival and decreases bacterial loads in an airway Pseudomonas aeruginosa infection in mice

The type III secretion system needle, tip, and translocon

Discovery and characterization of a water-soluble prodrug of a dual inhibitor of bacterial DNA Gyrase and Topoisomerase IV

A novel inhibitor of gyrase B is a potent drug candidate for treatment of tuberculosis and nontuberculosis mycobacterial infections

A new-class antibacterial-almost. Lessons in drug discovery and development: A critical analysis of more than 50 years of effort toward ATPase inhibitors of DNA Gyrase and Topoisomerase IV

In vitro susceptibility testing of a novel benzimidazole, SPR719, against nontuberculous mycobacteria

ATP-competitive DNA gyrase and topoisomerase IV inhibitors as antibacterial agents

Spero Therapeutics announces second quarter 2019 operating results and provides pipeline update

Recent progress in the development of small-molecule FtsZ inhibitors as chemical tools for the development of novel antibiotics

Mechanism of action of the cell-division inhibitor PC190723: Modulation of FtsZ assembly cooperativity

TAXIS secures NIH Funding (Press Release

An inhibitor of FtsZ with potent and selective antistaphylococcal activity

Creating an antibacterial with in vivo efficacy: synthesis and characterization of potent inhibitors of the bacterial cell division protein FtsZ with improved pharmaceutical properties

An improved small-molecule inhibitor of FtsZ with superior in vitro potency, drug-like properties, and in vivo efficacy

TAXIS acquires novel antimicrobial drug candidates from Biota

Pharmacokinetics and in vivo antistaphylococcal efficacy of TXY541, a 1-methylpiperidine-4-carboxamide prodrug of PC190723

TXA709, an FtsZ-targeting benzamide prodrug with improved pharmacokinetics and enhanced in vivo efficacy against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother

In vivo pharmacodynamic evaluation of an FtsZ inhibitor, TXA-709, and its active metabolite, TXA-707, in a murine neutropenic thigh infection mode

New and repurposed drugs

Alliance Clinical programs update (CPTR Annual Meeting

Identification of less lipophilic riminophenazine derivatives for the treatment of drug-resistant tuberculosis

Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis

Clofazimine: a useful antibiotic for drugresistant tuberculosis

In vitro and in vivo activities of the riminophenazine TBI-166 against Mycobacterium tuberculosis

Identifying regimens containing TBI-166, a new drug candidate against Mycobacterium tuberculosis in vitro and in vivo

Azaindoles: noncovalent DprE1 inhibitors from scaffold morphing efforts, kill Mycobacterium tuberculosis and are efficacious in vivo

Lead optimization of 1,4-azaindoles as antimycobacterial agents

1,4-Azaindole, a potential drug candidate for treatment of tuberculosis

TenNor's new drug for anaerobic bacterial infections, has been approved for clinical research

Highly efficient synthesis of a Staphylococcus aureus targeting payload to enable the first antibody-antibiotic conjugate

Novel antibody-antibiotic conjugate eliminates intracellular S. aureus

A phase 1, randomized, single-ascendingdose study to investigate the safety, tolerability, and pharmacokinetics of DSTA4637S, an anti-Staphylococcus aureus thiomab antibody-antibiotic conjugate, in healthy volunteers

Preclinical and translational pharmacokinetics of a novel THIOMAB™ antibody-antibiotic conjugate against Staphylococcus aureus

Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates

Naturally-occurring β-lactamase inhibitors with antibacterial activity

Clavulanic acid, a novel βlactam isolated from Streptomyces clavuligerus; X-ray crystal structure analysis

Clavulanic acid: a beta-lactamase-inhibiting beta-lactam from Streptomyces clavuligerus

Liquid chromatography-tandem mass spectrometry for the simultaneous quantitation of enmetazobactam and cefepime in human plasma

In vivo activities of simulated human doses of cefepime and cefepime-AAI101 against multidrugresistant Gram-negative Enterobacteriaceae

In vitro activity of cefepime/AAI101 and comparators against cefepime non-susceptible Enterobacteriaceae

ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii

Reversibility of covalent, broad-spectrum serine β-lactamase inhibition by the diazabicyclooctenone ETX2514

Pharmacokinetics, safety, and tolerability of intravenous durlobactam and sulbactam in subjects with renal impairment and healthy matched control subjects. Antimicrob Agents Chemother

Targeting multidrug-resistant Acinetobacter spp.: sulbactam and the diazabicyclooctenone β-lactamase inhibitor ETX2514 as a novel therapeutic agent

Frequency and mechanism of spontaneous resistance to sulbactam combined with the novel β-lactamase inhibitor ETX2514 in clinical isolates of Acinetobacter baumannii

Discovery of taniborbactam (VNRX-5133): A broadspectrum serine-and metallo-β-lactamase inhibitor for carbapenem-resistant bacterial infections

Bicyclic boronate VNRX-5133 inhibits metalloand serine-β-lactamases

OP0595, a new diazabicyclooctane: mode of action as a serine β-lactamase inhibitor, antibiotic and β-lactam 'enhancer

Efficacy of Human-simulated epithelial lining fluid exposure of meropenem-nacubactam combination against class a serine β-lactamase-producing Enterobacteriaceae in the neutropenic murine lung infection model

Interactions of OP0595, a novel triple-action diazabicyclooctane, with β-lactams against OP0595-resistant Enterobacteriaceae mutants

Fedora Pharmaceuticals and Meiji Seika Pharma sign basic agreement to establish NacuGen Therapeutics Inc., a joint venture to develop and commercialize nacubactam for bacterial infections

750M antibiotics deal as it re-embraces the field (Fierce Biotech 13

Fedora join forces to tackle increasing bacterial resistance to antibiotics: Roche licenses investigational beta-lactamase inhibitor OP0595, OP0595 targets beta-lactamase enzymes in combination with new or existing beta-lactam antibiotics to enhance their effectiveness in difficult-to-treat bacterial infections

Single-center evaluation of the pharmacokinetics of WCK 5222 (cefepime-zidebactam combination) in subjects with renal impairment

Strategic approaches to overcome resistance against Gram-negative pathogens using β-lactamase inhibitors and β-lactam enhancers: Activity of three novel diazabicyclooctanes WCK 5153, zidebactam (WCK 5107), and WCK 4234

WCK 5222 (cefepime/zidebactam) antimicrobial activity tested against Gram-negative organisms producing clinically relevant β-lactamases

Potent β-lactam enhancer activity of zidebactam and WCK 5153 against Acinetobacter baumannii, including carbapenemase-producing clinical isolates. Antimicrob Agents Chemother

Assessment of the in vivo efficacy of WCK 5222 (cefepime-zidebactam) against carbapenem-resistant Acinetobacter baumannii in the neutropenic murine lung infection model

In vivo efficacy of WCK 5222 (cefepime-zidebactam) against multidrug-resistant Pseudomonas aeruginosa in the neutropenic murine thigh infection model

Entasis Therapeutics announces initial ETX0282 phase 1 results (Press Release 13

Efficacy of cefpodoxime proxetil and ETX0282 in a murine UTI model with E. coli and K. pneumoniae (Poster P1991, 29th ECCMID Conference

inventors; Entasis Therapeutics, assignee. Beta-lactamase inhibitor compounds. United States patent US 20190202832

inventors; VenatoRx Pharmaceuticals, assignee. Beta-lactamase inhibitors. United States patent US 9

Pevear DC Ceftibuten/VNRX-7145, an orally bioavailable β-lactam/β-lactamase inhibitor combination active against serine-β-lactamase-producing Enterobacteriaceae

Strategic Portfolio Development (Press Release

Orally absorbed derivatives of the β-lactamase inhibitor avibactam. Design of novel prodrugs of sulfate containing drugs

Oral prodrugs of avibactam, medicinal chemistry, and synthesis of ARX-1796

How antibiotics kill bacteria: From targets to networks

Two for the price of one: Attacking the energeticmetabolic hub of mycobacteria to produce new chemotherapeutic agents

Bacterial metabolism and antibiotic efficacy

Physicochemical properties of antibacterial compounds: implications for drug discovery

Acknowledgements DLP is the recipient of an NHMRC Investigator