key: cord-0722762-km54wyh5
authors: Srinivasan, Ramanathan; Kannappan, Arunachalam; Shi, Chunlei; Lin, Xiangmin
title: Marine Bacterial Secondary Metabolites: A Treasure House for Structurally Unique and Effective Antimicrobial Compounds
date: 2021-09-23
journal: Mar Drugs
DOI: 10.3390/md19100530
sha: f8675ac0a92aa516e599bb2bb583ca104f2debd0
doc_id: 722762
cord_uid: km54wyh5

The prevalence of antimicrobial resistance reduces the effectiveness of antimicrobial drugs in preventing and treating infectious diseases caused by pathogenic organisms, such as bacteria, fungi, and viruses. Because of the burgeoning growth of microbes with antimicrobial-resistant traits, there is a dire need to identify and develop novel and effective antimicrobial agents to treat infections from antimicrobial-resistant strains. The marine environment is rich in ecological biodiversity and can be regarded as an untapped resource for prospecting novel bioactive compounds. Therefore, exploring the marine environment for antimicrobial agents plays a significant role in drug development and biomedical research. Several earlier scientific investigations have proven that bacterial diversity in the marine environment represents an emerging source of structurally unique and novel antimicrobial agents. There are several reports on marine bacterial secondary metabolites, and many are pharmacologically significant and have enormous promise for developing effective antimicrobial drugs to combat microbial infections in drug-resistant pathogens. In this review, we attempt to summarize published articles from the last twenty-five years (1996–2020) on antimicrobial secondary metabolites from marine bacteria evolved in marine environments, such as marine sediment, water, fauna, and flora.

Bacteria are ubiquitous, and they are vital for the preservation of the ecosystem in which we live. Only a small percentage of bacteria are pathogenic. However, the infections caused by pathogenic bacteria significantly affect public health [1, 2] . Bacterial infections are often more superficially controlled than fungal and viral infections because of the presence of an antibacterial drugs arsenal with growth inhibitory activity. However, the rapid development of bacterial resistance to antimicrobials is a pressing issue that surpasses the devastating effects of fungal and viral infections [1, 3] . The phenomenon of resistance is not equivalently spread across all bacterial species. However, the Infectious Disease Society of America (IDSA) has recognized six bacterial species as highly dangerous owing to their possible multidrug resistance mechanisms and pathogenicity [4] . Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter sp. are referred to as ESKAPE pathogens. These ESKAPE 

The phylum Actinobacteria is Gram-positive bacteria known for their pioneering efforts to synthesize a diverse array of valuable secondary metabolites. Actinobacteria are abundantly present in marine environments, where they serve an essential ecological role in recycling refractory biomaterials and producing novel bioactive compounds with pharmaceutical applications [76] . The abundance and distribution of Actinobacteria may vary among the diverse marine organisms. Most actinobacterial species are frequently isolated from bottom sediments, seashores, coastal waters, mollusks, fish, seaweeds, sponges, and mangroves [77] [78] [79] . According to studies employing culture-dependent and independent molecular methods, abundant novel actinobacterial communities are associated with sponges [80] [81] [82] . Further, the phylum Actinobacteria are represented by one-sixth of the sponge-associated bacterial sequences in public databases, suggesting that Actinobacteria are a significant phylum among sponge-associated bacteria [83] . Although they are commonly found in bottom sediments, they rarely account for more than 10% of the live microflora.

Marine environments are home to many actinobacterial taxa, including Micromonospora, Nocardiopsis, Nocardia, Plantactinospora, Solwaraspora, Saccharomonospora, Streptomyces, and Salinispora [84] . Among these, Streptomyces is a widespread actinobacterial genus found in marine environments. This actinobacterial genus shows a wide range of physiological and metabolic characteristics, including the ability to produce a wide array of extracellular enzymes and secondary metabolites, many of which are exploited by the pharmaceutical industry [85] . Recently, Contreras-Castro et al. isolated 75 Actinobacteria from marine sediment in Punta Arena de La Ventana, Mexico. A total of seventy-one isolates were confirmed belonging to the genus Salinispora by 16S rRNA gene identification and multilocus sequence analysis. They subsequently evaluated the antibacterial potential of supernatants from several Salinispora strains, revealing that supernatants from ten Salinispora strains had excellent growth inhibition activity against ESKAPE pathogens [86] . Similarly, in another study, a total of 148 Actinobacteria were isolated from Diu Island's intertidal sediments in the Arabian Sea [79] . All the isolates were categorized within actinobacterial taxa: Glycomycetales, Micromonospora, Nocardia, Nocardiopsis, Pseudonocardiales, and Streptomyces. Among the 148 isolates, 62 different actinobacterial isolates were subsequently tested for their antibacterial activity against Bacillus subtilis, Escherichia coli, K. pneumonia, and S. aureus. Out of these, 23 isolates were positive for one or more of the tested bacterial pathogens. Yücel and Yamaç revealed the antibacterial efficacy of Streptomyces sp. 1492 against drug-resistant bacterial pathogens, such as E. faecium, S. aureus, and A. baumannii [87] . Chlorocatechelins are novel siderophores with chlorinated catecholate complexes and an acylguanidine structure [88] . Chlorocatechelin A (Figure 2 , Compound 1) extracted from Streptomyces sp. inhibited the growth of a wide range of bacterial and fungal pathogens. The new Streptomyces sp. MUSC 135T strain was isolated from mangrove forest sediment on Peninsular Malaysia's east coast. It can produce the broad-spectrum antibiotic molecule bacitracin A ( Figure 2, Compound 2) , effective against S. aureus ATCC BAA-44 [89, 90] . Novel bioactive compounds, such as indole-3-lactic acid ( Figure 2 , Compound 3) and phenylacetic acid ( Figure 2, Compound 4) , were isolated from the fermentation broth of Streptomyces CTF9. In prescreening studies, the bioactive compounds containing Streptomyces extract exhibited strong antifungal activity against C. albicans and Mucor miehei [91] . 

Bacteroidetes is the third most common phylum in the oceans, behind Proteobacteria and Cyanobacteria [92] . Bacteroidia, Cytophaga, Flavobacteria, and Sphingobacteria are the four major classes of the Bacteroidetes phylum. Bacteroidetes is classified into major Gram-negative, rod-shaped, and non-spore-forming bacteria that can live in aerobic and anaerobic environments [93] . Groups of bacteria related to phylum Bacteroidetes may be found in abiotic environments, such as marine sediments, marine seawater, and soil, and biotic habitats, such as animal skin and intestines [94] .

A recent comparative genomic analysis revealed abundant Flavobacterium in the marine environment, often associated with fish, marine invertebrates, and algae. According to their genome mining data, the bacteria belong to the genus Flavobacterium have a broad secondary metabolite biosynthesis arsenal, with a high frequency of gene cluster-coding pathways for the production of several pharmacological activities, including antimicrobial ones. Further, they have done antimicrobial phenotypic assays to confirm their genomederived data [95] . The antimicrobial substances producing marine bacteria belonging to the genus Flavobacterium were isolated from marine invertebrate samples collected from Ancon Bay, Lima, Peru. The bacterial isolates from the genus Flavobacterium exhibited intense antibacterial activity against many human bacterial pathogens [96] . The biotechnological potential of microorganism-derived glucose dehydrogenase enzymes has attracted much interest because of their antimicrobial potential in various industrial applications [97] . The membrane fraction of the marine bacterium Cytophaga marinoflava IFO 14170 yielded a new glucose dehydrogenase [98] .

Cyanobacteria are the only bacterial phylum that derive their energy from the process of photosynthesis. Further, it is the only photosynthetic prokaryote group capable of producing oxygen and absorbing CO 2 [99] . The marine Cyanobacteria are a powerful nonconventional source of bioactive compounds with a bright and hopeful future in drug development for treating various diseases [100] . Richard E. Moore's groundbreaking research at the University of Hawaii from the 1970s to the early 2000s shows marine Cyanobacteria to be a potent source of secondary metabolites [101] . Many of these secondary metabolites are distinctively combined with the structural characteristics of peptides and lipids before being further functionalized with atypical oxidations, halogenations, and methylations [102] . Moreover, most of these secondary metabolites are nitrogen-based compounds produced by multimodular nonribosomal polypeptide [100] . The secondary metabolites of marine cyanobacteria have been previously well-reported for their pharmacological activities, such as antibacterial, antiviral, antifungal, anticancer, and antiplasmodium properties [103] .

The secondary metabolites ambiguine-K and M isonitrile ( Figure 3 , Compounds 5 and 6), isolated from the marine cyanobacterium Fischerella ambigua (UTEX 1903), have exhibited intense antibacterial activity against Mycobacterium tuberculosis with MIC values of 6.6 and 7.5 µM, respectively [104] . The novel alkylphenols, anaephenes A-C, were isolated from the cyanobacterium Hormoscilla sp. It showed moderate growth inhibition against S. aureus [105] . At the concentrations of 22, 6.1, and 22 µg/mL, respectively, anaephenes A, B, and C inhibited the complete visible growth of the S. aureus. It seems that there are just a few antiviral drugs that were isolated from marine bacteria when compared to the antibacterial and antifungal drugs. Among them, a maximum of the reported antiviral compounds was derived from marine Cyanobacteria. Glycolipids are found in prokaryotic and eukaryotic photosynthetic organisms, where they are connected with thylakoid membranes. Glycolipids are also found in the heterocystous cell walls of Cyanobacteria [106] . Glycolipids have been found to have distinct antiviral activity in many investigations [107, 108] . Gustafson et al. tested extracts of marine Cyanobacteria (Phormidium tenue and Yngbya lagerheimii) for HIV-1 inhibition using a tetrazolium-based microculture. As a result, sulfonic acid-containing glycolipids were identified as a novel family of HIV-1-inhibiting agents [109] . The novel acylated diglycolipids, and diacylated sulfoglycolipids, were derived from the Cyanobacterium Oscillatoria raoi and Scytonema sp., respectively. Both of these glycolipids inhibited HIV-1 reverse transcriptase enzymatic activity at a final concentration of 10 µM [106] . The sulfoquinovosylpranosyl lipids from lipophilic extracts of Cyanobacteria were responsible for the strong in vitro suppression of HIV-1 enzymatic activity. With a half-maximal inhibitory concentration (IC50) as low as 24 nM, these sulfolipids effectively and selectively blocked the DNA polymerase activity of HIV-1 reverse transcriptase [108] . Ayehunie et al. demonstrated that an aqueous extract of Cyanobacterium (Arthrospira platensis) containing polysaccharides suppressed syncytium formation and HIV-1 replication in human PBMC, T-cell lines, and Langerhans cells at nontoxic concentrations [110] . Calcium spirulan, a sulfated polysaccharide, was isolated from the aqueous extract of Spirulina platensis marine blue-green alga. Further, the inhibitory effect of calcium spirulan on a viral replication of measles, HIV-1, herpes simplex virus-1 (HSV-1), mumps, polio, and influenza A was assessed through different cell lines. Calcium spirulan has been shown to impede the reproduction of several enveloped viruses, including HIV-1, HSV-1, influenza A, mumps, and measles. It clearly shows that the calcium spirulan limited the viral penetration into the host cells in a selective manner [111] . Boyd et al. have isolated virucidal protein (cyanovirin-N) from the aqueous cellular extract of Cyanobacterium (Nostoc ellipsosporum). The cyanovirin-N inhibited primate retrovirus multiplication (HIV-1 and HIV-2) in vitro at nanomolar concentrations. Cyanovirin-N exerts these antiviral effects through interactions with the viral envelope glycoprotein that seem to be preserved [112] . 

Firmicutes is a phylum of Gram-positive bacteria. Few have a permeable pseudo-outer membrane that leads them to stain Gram-negative. Due to their ecological variety and unique physiological and molecular features, these bacteria have received much attention in recent decades. They offer a lot of promise for biotechnological applications. Bacillus is one of the most important groups of Firmicutes. Bacillus sp. has a high-temperature tolerance and can grow quickly in liquid culture. Bacillus species are frequently isolated from marine sediment samples and other marine habitats [113, 114] .

Recently, a novel oxatetracyclo ketone antimicrobial compound containing B. stercoris MBTDCMFRI Ba37 strain was isolated from estuarine habitats. The isolated compound inhibited the growth of aquatic bacterial pathogens belonging to the genera Aeromonas and Vibrio [115] . Further, a novel antagonistic secondary metabolite, bacilysin ( 

Planctomycetes is a phylum of bacteria with a low frequency of occurrence. This bacterial group is often found in freshwater, soil, and marine environments. Planctomycetes may be free-living or adhere to biotic and abiotic surfaces [118] . Bacteria belonging to the phylum Planctomycetes are critical components of the marine nitrogen and carbon cycles, acting as scavengers after phototrophic blooms [119] . An exploration of Planctomycetes' genome revealed the possibility of their producing antimicrobial polyketides, nonribosomal peptides, terpenoids, and bacteriocins. According to mass spectrometry studies, the unique bacteria of this group have also produced a new class of antimicrobial compounds [120, 121] .

In a recent study, stieleriacine, a novel class of N-acylated tyrosines, was isolated from the marine Planctomycete strain Stieleria maiorica Mal15 T . It reduced the growth and biofilm of the producing strain, S. maiorica Mal15 T , and the co-occurring marine bacterial species, respectively [122] . Similarly, in another study, N-acylated dehydrotyrosine derivative compound, namely, stieleriacine D, was isolated from marine Planctomycete strain S. neptunia sp. nov. It inhibited the growth of S. aureus and Micrococcus luteus at the concentrations of 16.7 and 66.7 µg/mL, respectively [119] .

Proteobacteria is the most diverse phylum of Gram-negative bacteria. The group is split into six classes, some identified by Greek letters spanning from Alpha to Epsilon, while others are known as Oligoflexia and Acidithiobacillia [70] . Previous research has shown that Proteobacteria may dominate microbial communities, even in deep-sea environments [123, 124] . The marine bacterial phyla Proteobacteria are frequently reported as major bioactive chemical producers in marine macro-organisms. They can produce biologically active molecules with antibacterial, antiviral, antibiofilm, antifouling, and anticancer activities [125] .

The Pseudoalteromonas species, associated with marine invertebrates and seaweed, have been identified as producers of the enormously potent antibiotic molecule, thiomarinol [126] . Recently, Dat et al. have examined the diversity and antimicrobial activity of cultivable bacteria in Vietnamese sponges. A total of 460 cultivable bacterial isolates were isolated from 18 marine sponges, in which nearly 58% of the bacteria belonged to the phylum Proteobacteria. Moreover, they have identified secondary metabolites, such as macrolactin A ( Figure 5, Compound 9) , and macrolactin H ( Figure 5 , Compound 10), as the major bioactive compounds. The isolated compounds exhibited strong antibacterial actions against a wide range of pathogenic organisms [127] . 

Since the 1940s, the soil has been viewed as the primary source for isolating antibiotic compounds. A shift from soil to other sources, such as marine sediment, has been seen in recent decades [128] . Sediment refers to any solid particle of inorganic or organic materials. Marine sediments include those found near the shore, such as rocks and cobbles, seashell fragments, and sand, and in the mud at the bottom of ocean waters. Furthermore, the continental and oceanic crust, volcanoes, chemical processes, outer space, microorganisms, and plants and animals, all influence the formation of marine sediments [129] . Marine sediments may be classified into two types based on their source area: near-shore sediments and deep-sea sediments. Numerous bacterial strains isolated from near-shore sediments are closely related to strains previously identified in soil [130] . This is because, unsurprisingly, many studies on the isolation of marine bacterial isolates from near-shore sediments have yielded the known secondary metabolites. As a result, access to marine deep-sea sediments has become a priority, increasing the probability of discovering novel marine bacterial isolates [70, 128] .

Macrolactins are 24-membered lactone natural products with several pharmacological activities, making them attractive therapeutic candidates. They are mainly generated by marine-derived microorganisms [128] . A Macrolactin class of antibacterial and antiviral drugs were isolated from unclassified deep-sea sediment marine bacteria. Among the different macrolactins isolated, macrolactin A showed potent antibacterial activity against S. aureus and B. subtilis. Additionally, macrolactin A was an effective inhibitor of the HSV type-1 (strain LL) and type-2 viruses (strain G), with IC50 values of 5.0 and 8.3 µg/mL, respectively [129] . Marine Streptomyces sp. B7064 was isolated in mangrove sediment in Pohoiki, Hawaii, and was found to produce chalcomycin ( Figure 6 , Compound 11), a novel macrolide antibiotic. The compound exhibited potent antibacterial activity against S. aureus, E coli, and B. subtilis, with minimum inhibitory concentration (MIC) values of 0.39, 750, and 6.25 µg/mL, respectively [131] . Aborycin ( Figure 6 , Compound 12) was extracted and identified from the Streptomyces sp., which was isolated from the deep-sea sediments of the South China Sea [132] . With MIC values ranging from 8.0-128 µg/mL, the compound showed moderate bacteriostatic activity against different strains of S. aureus. Further, this secondary metabolite inhibited E. faecalis and B. thuringiensis at the MIC values of 8.0 and 2.0 µg/mL, respectively. A novel polyketide compound abyssomicin Y ( Figure 6 , Compound 13) was isolated from the marine-sediment-derived Verrucosispora strain MS100137, which exhibited potent antiviral activity against the influenza A virus at a concentration of 10 µM [133] . Certain marine bacteria have great potential for producing varied and remarkable characteristics, such as pigment production [134] . These marine-pigmented bacteria have been shown to possess various biological functions, including antibacterial, anticancer, antifungal, and immunosuppressive functions [135] . The red-pigmented prodigiosin compound was first isolated and identified as a secondary metabolite from the ubiquitous bacteria Serratia marcescens [136] . Apart from S. marcescens, many marine bacteria belonging to the genera Actinomadura, Pseudoalteromonas, Pseudomonas, and Streptomyces have been reported to produce red-pigmented prodigiosin and related compounds [137] [138] [139] . The Hahella sp. isolated from the sediment sample from Nagasaki Prefecture, Japan, secreted enormous amounts of redpigmented prodigiosin (Figure 7, Compound 14) , which showed excellent antibacterial activity against different strains of S. aureus [140] . The polyketide ansalactams A-D are radically modified ansamycins that were obtained from the marine sediment culture of Streptomyces sp. CNH189. The antibacterial activity of ansalactams B, C, and D ( Figure 7 , Compounds 15-17) against S. aureus was moderate, with MICs of 31.2, 31.2, and 62.5 µg/mL, respectively. In contrast, ansalactam A was inactive up to 100 µg/mL [141] .

Marine bacteria are the major source of structurally distinct and biologically significant nonribosomal peptides, particularly cyclopeptide derivatives. Yang et al. isolated three cyclopeptides derivatives, the halolitoralins A, B, and C, from the marine-sedimentderived Halobacillus litoralis YS3106 strain. In comparison to the other two cyclopeptides, halolitoralin A ( The cocultivation of two or more microorganisms has gained increased attention due to the possibility of finding novel bioactive natural compounds [146] . The cocultivation of marine sediment-derived bacterial strains, such as Janthinobacterium sp. ZZ145 and ZZ148, induced the production of two novel polyketides, including janthinopolyenemycins A and B (Figure 9 , Compounds 24 and 25). Furthermore, both janthinopolyenemycins A and B exhibited excellent antifungal activity against C. albicans with a MIC value of 15.6 µg/mL [147] . In another study, Cho et al. isolated the actinomycete strain (S. cinnabarinus PK209) from marine sediment collected from the coast of Korea. They cocultivated the S. cinnabarinus PK209 with Alteromonas sp. to induce the production of the diterpene compound lobocompactol (Figure 9, Compound 26) . Then, the overproduced lobocompactol was tested for their growth inhibitory potential. The obtained data revealed that lobocompactol acted as an antifouling agent on macroalga Ulva pertusa by preventing the attachment and growth of different fouling bacteria [148] . 

Microbial life in marine water is diverse, with bacteria, viruses, fungi, and spores being the most prevalent [40] . Novel antibacterial dipeptide compounds, such as unnarmicins A and C, were extracted from marine bacterium Photobacterium sp. MBIC06485. This marine bacterial strain was isolated from the coastal seawater collected from Onna Beach, Okinawa, Japan. The isolated dipeptide compounds selectively inhibited the two marine environmental pathogenic strains, Alphaproteobacteria and Pseudovibrio [149] . A bioassay-guided fractionation of a fermentation broth of Pseudonocardia carboxydivorans M-227, isolated from deep-seawater in the Avilés submarine canyon, disclosed the presence of two antibiotic molecules, branimycins B and C ( Figure 10 , Compounds 27 and 28). These two antibiotic molecules exhibited moderate to substantial antibacterial activities against different Grampositive and Gram-negative bacterial pathogens [150] . The marine bacteria Pseudomonas UJ-6, isolated from the seawater sample, has been shown to possess the secondary metabolite 1-acetyl-beta-corboline ( Figure 10, Compound 29) . Further, the bioactive compound extracted from Pseudomonas UJ-6 had antibacterial action against S. aureus with the MIC range of 32-128 µg/mL [151] . Arisostatin B (Figure 10, Compound 30) , a novel tetroarcin antibiotic, was extracted from the cultivated broth of the Micromonospora sp. obtained from sea water in Toyama Bay, Japan. At concentrations of 3.1, 25, and 50 µg/mL, respectively, arisostatin B inhibited the growth of M. luteus, B. subtilis, and S. aureus [152] . Arena et al. extracted the exopolysaccharide (EPS) from B. licheniformis, isolated from shallow marine water from the hot spring on Vulcano Island, Italy. The extracted EPS potentially enhanced the innate immunity of human peripheral blood mononuclear cells (PBMC) against the herpesvirus [HSV-1] infection by promoting Th1-type cytokine polarization [153] . Furthermore, the same research group extracted EPS from the marine Geobacillus thermodenitrificans, isolated from the deep-sea vent of Vulcano Island, Italy. They found that the EPS treatment inhibited HSV-1 multiplication in PBMC by elevating the amounts of IL-12, IL-18, TNF-, and IFN- [154] . In addition to these, several marine bacterial isolates derived from marine sediments and water have been well-reported for their antimicrobial activities, which are tabulated in Table 1 . 

Marine fauna is extremely diverse and encompasses living organisms from microscopic zooplankton to blue whales. The marine fauna classification includes all animals and living organisms present in the ocean, regardless of their size. They play critical roles in maintaining key ecological processes and functions within the marine ecosystem. Apart from these, certain marine fauna act as a treasure house for synthesizing several novel bioactive compounds. The following sections intensely discuss the antimicrobial potentials of marine bacteria associated with certain important marine fauna, such as sponges, corals, and mollusks.

Marine sponges contribute significantly to benthic communities worldwide, both in biomass and their ability to affect benthic or pelagic processes [197] . Sponges are abundant in tropical reefs, but they also inhabit polar regions, the deep sea, and freshwater lakes and rivers. They are one of the oldest multicellular invertebrates and exist in a broad range of colors and textures. To date, over 8000 sponge species have been identified in various marine and freshwater environments [198] . Marine sponges are habitat to a diverse array of microbial communities, including bacteria, fungi, archaea, and viruses, which provide an essential source of natural products. Microbial biomass may take up to 35% of the sponge's volume. These sponges are classified as "high-microbial abundance". The true origin of several sponge-derived secondary metabolites remains unclear to date. Secondary metabolites may be generated by sponges, their microbial symbionts, or the interactions between sponges and symbionts [199] . Interestingly, many studies have shown that several bioactive compounds discovered in sponges may be of bacterial origin, according to the chemical structural resemblance to those found in terrestrial and marine microorganisms [197, 200] . It suggests that sponge-associated bacteria, rather than the host, are the real producers. Furthermore, these symbiotic bacteria also play a significant role in the health and survival of marine sponges [201] . As a result, many researchers concentrate their efforts on sponge-associated bacteria, which may be used to screen and isolate bioactive compounds.

Recently, Altug et al. isolated the sponge-associated bacteria collected from the Sea of Marmara, Turkey. They then assessed the antibacterial potential of the methanolic extract of marine sponge-associated bacteria against different bacterial pathogens, such as S. aureus, Vibrio vulnificus, and E. coli. At the tested concentrations (7.8 to 1000 µg/mL), the extracts significantly inhibited the growth of all the tested bacterial pathogens. Finally, they identified this efficient sponge-associated bacterium related to B. cereus through molecular identification [202] . The majority of actinomycetes obtained from marine sources are believed to have originated from marine sponges, with Streptomyces being the most common species [203] . Numerous studies have shown that the isolation of several novel bioactive compounds from Streptomyces is associated with marine sponges [204] [205] [206] . Around 22% of the bioactive compounds are isolated from marine sponges associated with actinomycetes. In a recent study, Fahmy et al. have isolated the antimicrobial compounds from Streptomyces sp. associated with the marine sponge collected from the Egyptian Red Sea coast [62] . In another recent work, a novel antiviral compound, namely homoseongomycin, was isolated from marine sponge-associated actinomycete bacteria K3-1. It showed potent antiviral activity against alphaviruses, such as the eastern and Venezuelan equine encephalitis viruses, with 50% effective concentrations of 1.2 and 8.6 µM, respectively [207] . Mitova et al. isolated a novel cyclopeptide compound, namely, cyclo-(glycyl-L-seryl-Lprolyl-L-glutamyl) ( Figure 11 , Compound 31) from the extract of marine Agrobacterium (Ruegeria strain) associated with the sponge Suberites domuncula. The isolated cyclopeptide has exhibited potent antibacterial activity against B. subtilis at the concentration of 25 µg/mL [208] . In another study, novel thiopeptide antibiotic substances, namely, YM-266183 and YM-266184 ( Figure 11 , Compounds 32 and 33), were isolated from marine bacteria B. cereus QN03323 associated with the sponge Halichondria japonica. Further, both of these thiopeptide antibiotic substances have shown excellent growth inhibitory potential against Gram-positive bacterial pathogens [209] . A thiazolyl peptide derivative compound, kocurin ( Figure 11, Compound 34) , was extracted from the culture broth of Kocuria palustris. This bacterial strain was isolated from a marine sponge sample collected in the Florida Keys, United States of America (USA), and the compound kocurin showed excellent antibacterial and antifungal activities against certain bacterial and fungal pathogens [210] .

The cocultivation of bacterial isolates obtained from marine sponges, such as Rhodococcus sp. and Micromonospora sp., stimulated the synthesis of a novel antibiotic molecule, keyicin ( Figure 12, Compound 35) . Further, the extracted bioactive compound keyicin selectively inhibited the growth of Gram-positive bacterial pathogens, especially Mycobacterium sp. and Rhodococcus sp. [211] . Similarly, the coculture of actinomycete (S. rochei MB037) derived from a marine sponge (Dysidea arenaria) with fungus (Rhinocladiella similis 35) stimulated the production of borrelidin J ( Figure 12, Compound 36) . The extracted fatty acid compound borrelidin J exhibited profound antibacterial action against S. aureus with a MIC value of 0.195 µg/mL [212] . In another study, the cocultivation of two marine sponge-derived actinomycetes, Nocardiopsis sp. RV163 and Actinokineospora sp. EG49, induced the production of ten different secondary metabolites related to β-carboline, diketopiperazine, and angucycline derivatives. Among them, the prenylated derivative compound 1,6-dihydroxyphenazine ( Figure 12, Compound 37) only showed antibacterial activity against Bacillus sp. P25 [213] .

Corals, among marine organisms, are potential producers of marine bioactive compounds and have received a lot of attention. Deep-sea corals produce a variety of bioactive natural products with structurally diverse properties [214] . Microorganisms, primarily bacteria, have been shown to colonize different sections of coral tissues (gastrovascular cavity, mucus layer, and skeleton) and to have a role in coral development, health, and stress tolerance [215] . Further, earlier studies show that the coral microbiome protects coral hosts by producing antimicrobial agents, suppressing pathogenic metabolic enzymes, interrupting cell-to-cell communication systems, and competitively eliminating pathogens from the host cell surfaces [216] [217] [218] [219] . Many structurally distinct bioactive compounds with a wide variety of pharmacological activities, including antimicrobial compounds, may be produced by coral-associated bacteria against a wide range of pathogenic organisms [218] . Figure 13, Compound 38) , from the acidified ethyl acetate extract of S. cyaneofuscatus. It showed potent antibacterial activity against Grampositive bacterial pathogens, such as S. aureus, E. faecalis, and E. faecium, at the concentration of 0.03 µg/mL [220] . Watasemycin-A, aerugine, and pulicatin-G are three thiazole derivatives extracted from Streptomyces sp. OUCMDZ-1703, a coral-associated actinomycetes strain. Watasemycin-A ( Figure 13, Compound 39) and aerugine ( Figure 13, Compound 40) were the first compounds that exhibited strong antibacterial action against different clinical strains of S. aureus with the MIC value of 7.81 µg/mL [221] . Sarmiento-Vizcaíno et al. collected 87 deep-sea coral reef samples from the submarine Avilés Canyon, Spain. They then isolated 18 different cultivable Actinobacteria from the coral samples and tested their antimicrobial potential. The obtained results revealed that the isolated deep-sea Actinobacteria exhibited both antibacterial and antifungal activities [222] . The strain Micromonospora marina was isolated from a soft coral and produced a novel depsipeptide compound, namely, thiocoraline ( Figure 13, Compound 41) . With a MIC value of 0.05 µg/mL, thiocoraline exhibited strong antibiotic action against Gram-positive bacterial pathogens, such as B. subtilis, and S. aureus [223] . 

Mollusks are the largest marine phylum, accounting for 23% of marine organisms. Mollusks with shells are assumed to be low in secondary metabolites, although they may produce peptide toxins for both defense and predation [70] . Secondary metabolites help to protect mollusks even without shells. The systematic structural analysis of certain secondary metabolites has indicated that these small chemical compounds are produced by symbiotic bacteria, not by mollusks [224] .

Bacicyclin (Figure 13, Compound 42) , a novel cyclic hexapeptide, was identified from Bacillus sp. BC028. This marine bacterial strain was isolated from the common mussel (Mytilus edulis). It has antibacterial properties against S. aureus and E. faecalis, with MIC values of 12 and 8 µM, respectively [225] . S. sampsonii SCSIO 054 is a marine-gastropodmollusk-associated bacteria with a biosynthetic gene cluster that governs the synthesis of the antibacterial compound julichromes [226] . The Hawaiian bobtail squid contains symbiotic bacterial consortia in the auxiliary nidamental gland (a female reproductive system that shields eggs from fouling microorganisms). Nineteen bacterial isolates were isolated from these bacterial consortia. Further, these isolates were tested for their ability to inhibit the growth of Gram-positive and Gram-negative bacterial pathogens. Among these, the two bacterial isolates, Pseudoalteromonas sp. JC28 and Leisingera sp. ANG59, showed potential antibacterial activity against tested bacteria [227] .

In addition to these, the antimicrobial activity of numerous bacteria associated with different marine fauna has been extensively documented, as shown in Table 2 . 

Like marine fauna, marine flora is also abundant in nature. Some are so tiny and can only be seen with the aid of a microscope. They have various living forms; some float, while others are attached to different surfaces with a holdfast. Organisms in marine flora are rich in minerals and provide nutraceuticals that can be added as the necessary components of the diet. In general, the host-microbe interaction plays a crucial role in host adaptation to different environments [46] . This kind of microbe interaction, especially with plants, results in the production of novel compounds with potential applications in several areas, such as medicine, environmental protection, bioremediation, and others [47] . Hence, the following sections describes the potential antimicrobial compounds from bacteria associated with certain marine flora, such as seaweeds, seagrasses, and mangroves.

Seaweeds (macroalgae) are photosynthetic organisms with an essential role in sustaining the marine ecosystem. Seaweeds are divided into three types based on their pigmentation. They are classified as green algae, brown algae, and red algae. Brown seaweeds contain fucoxanthin and chlorophyll a and c pigments, red seaweeds contain allophycocyanin, phycoerythrin, xanthophylls, and chlorophyll-a pigments, and green seaweeds contain xanthophylls and chlorophyll a and b pigments [244, 245] . The seaweed surfaces offer an ideal substrate for microorganisms to colonize, and for various secret organic compounds that serve as nutrients for microorganisms to proliferate. Therefore, they provide an excellent habitat for several microorganisms [246] . Numerous studies have shown that seaweed-associated bacteria are essential for determining the host's basic morphology, growth, and development [40, 76] . Seaweeds may also be viewed as a source of microbial nutrients, which results in intense competition between diverse microbial populations [66] . Moreover, seaweeds provide nutrients for associated microorganisms which, in turn, defends them from biological threats, such as pathogenic and fouling organisms, via the synthesis and release of bioactive substances [247] . Microbial communities that live on the surfaces of seaweeds are very complex and dynamic, consisting of a diverse array of microorganisms, such as bacteria, fungi, protozoa, and diatoms [248, 249] . Numerous investigations have shown that bacteria associated with seaweeds are unique from bacteria present in seawater. These bacteria mostly come under the phyla of Actinobacteria, Bacteroidetes, Firmicutes, Planctomycetes, and Proteobacteria [250, 251] .

A new cyclic tetrapeptide compound, namely, cyclo-[phenylalanyl-prolyl-leucylprolyl] (Figure 14, Compound 43) , was identified from marine bacteria Pseudomonas sp. associated with the seaweed (Diginea sp.) that had excellent growth inhibitory potential against V. anguillarum and B. subtilis [252] . Franks et al. isolated the marine bacterium P. tunicata from the surface of U. australis. The antifungal compounds produced by P. tunicata provide a competitive edge over marine fungi during surface colonization. Further, tambjamine is a yellow-pigmented chemical molecule from P. tunicate that seems to have antifungal activity [253, 254] . The novel magnesium-containing antibiotic molecule, magnesidin A ( Figure 14, Compound 44) , was isolated from the marine bacterium P. magnesiorubra associated with the seaweed Caulerpa peltata. It selectively inhibited the growth of Staphylococcus sp. and Bacillus sp. [255] . Another bioactive compound, namely, 2, 4-diacetylphloroglucinol ( Figure 14, Compound 45) , was isolated from a novel Pseudomonas sp. AMSA. This surface-associated bacterial strain was isolated from the Ceratodyction spongiosum and significantly hindered S. aureus growth at the concentration of 4 mg/L [256] . Ravisankar et al. identified an alkaloid compound from Pseudomonas sp. associated with the seaweed Padina tetrastromatica. At a dosage of 300 µg, this bioactive compound inhibited the growth of Gram-negative bacterial pathogens, such as P. aeruginosa and K. pneumoniae, with an inhibitory zone of 10 and 15 mm, respectively [257] . Pelagiobacter variabilis, a novel marine bacterium, was isolated from the macroalga Pocockiella variegata. This bacterium produces a pelagiomicin A to C series of chemical molecules. Pelagiomicin A (Figure 14, Compound 46) showed potent antibacterial activity against a wide range of Gram-positive and Gram-negative bacterial pathogens [258] . 

Seagrasses provide major habitats for marine microorganisms and have a primary ecological function in coastal regions worldwide. Seagrasses are a diverse species of angiosperms found in the ocean along with macroalgae [259] . Generally, the marine habitat is often used as a nursery by various fish species [260] . The direct contact between animal and plant cells has been shown to promote metabolic pathways in microbes associated with seagrasses. Further, microbiological investigations confirm this theory by demonstrating that the microbial activity of the seagrass-associated holobiont is greater than that of the microbial community grown in a nonvegetated region [251] . Seagrasses have a large proportion of secondary metabolites, such as fatty acids and polyphenols, which are essential for adaptation to biotic and abiotic habitats, as well as the defense mechanism [261] . Moreover, microorganisms associated with seagrasses may preserve their environment by producing bioactive compounds that defend against biological threats, such as pathogenic and fouling organisms. For the same reason, they were recognized as a source of novel bioactive compounds in abundance [262] .

A total of 162 rhizome and endophytic bacteria isolates were enumerated from marine seagrass Halodule uninervis collected from the coastal zone of Jeddah, Saudi Arabia. In an in vitro assay, antifungal screening of isolated bacteria showed 19 strains capable of inhibiting the growth of four pathogenic fungi: Rhizoctonia solani, Phytophthora capsici, Pythium ultimum, and Pyricularia oryzae [263] . A recent study reported the isolation and genotypic identification of marine epiphytic bacteria with potent antibacterial activity from the Kuicheai seagrass (H. uninervis). Bacillus, Oceanimonas, Paenibacillus, and Planomicrobium were among the four genera of epiphytic bacteria identified. Using the perpendicular streak technique, Oceanimonas sp. PSS 241 was shown to have effective antibacterial activity against pathogenic S. aureus [264] .

Mangroves occupy 60-70% of the world's tropical and subtropical coastlines. This unique environment is a habitat for a diverse array of microorganisms. Microorganisms associated with mangroves may withstand certain changes in physicochemical environments, particularly in high-saline conditions [265] . As a result, they are critical components of this marine ecosystem. Apart from their critical function in ecological balance maintenance and biogeochemical processes, mangrove-associated microbes have a higher biotechnological potential in various fields, including pharmaceutical industries [251] . Marine microorganisms thrive in the lower portion of trunks and the aerating roots of mangrove plants that are permanently or intermittently immersed in saltwater. On the other hand, terrestrial microorganisms are often found in the upper portions of mangrove-aerating roots and trunks [266] .

The bacteria associated with mangroves, particularly Actinobacteria, are a unique and neglected source of natural pharmaceutical products. There is substantial data from diverse mangrove forests worldwide indicating Actinobacteria's widespread distribution and enormous promise in the pharmaceutical sector [251, 267] . The presence of actinomycetes has been well-described in a variety of mangrove environments around the world. In an earlier study, 23 actinomycete species were identified in the Pichavaram mangrove, India, most assigned to the genus Streptomyces [268] . In another study, a total of 518 Streptomyces isolates were identified in mangrove habitats near Porto Novo, India, by Laksmanaperumalsamy et al. [269] . Eccleston et al. revealed the wide spread of actinomycetes belonging to the genus Micromonospora in the mangrove plants of Australia's Sunshine Coast [270] . Similarly, Xie et al. and Huang et al. reported the isolation of a rifamycin-producing Micromonospora from mangroves in the South China Sea [271, 272] . Retnowati identified an actinomycete, Streptomyces sp., in mangrove soil on the eastern coast of Surabaya, Indonesia. It inhibited the growth of both Gram-positive and Gramnegative bacterial pathogens [273] . Santhi and Jebakumar reported that Streptomyces sp. isolated from mangrove sediment had profound antibacterial activity against S. aureus and Salmonella typhi [274] .

Likewise, as shown in Table 3 , the antimicrobial activity of several bacteria associated with different marine flora has been comprehensively documented. 

Modern advancements in genome sequencing have revealed that microorganisms could produce much more structurally diverse secondary metabolites, owing to several putative biosynthetic gene clusters (BGCs) that encode for secondary metabolites that are not observed under conventional culture conditions [294] . BGCs are composed of a group of genes that collectively code for the synthesis of one or more specific metabolites [295] . These clusters are needed to make a wide range of structurally varied compounds, such as polyketides and nonribosomal peptides. Several methods have been developed in the past decade to trigger these cryptic biosynthetic pathways and stimulate the synthesis of novel secondary metabolites from microorganisms [296] . Polyketide synthases (PKS) and nonribosomal peptide synthases (NRPS) are two examples of complex enzymatic machinery that have been shown to be responsible for the synthesis of marine bacterial bioactive secondary metabolites. Recently, Konstantinou et al. confirmed the potential of sponge-associated Cyanobacteria extracts from various taxonomic groups to produce antibacterial activity against S. aureus [297] . Moreover, they have performed phylogenetic analysis and molecular screening for genes encoding PKS and NRPS on sponge-associated Cyanobacteria. The obtained data reveal that the genes responsible for PKS were more ubiquitous than those responsible for NRPS. Graça et al. performed the molecular and bioactivity assays to evaluate the antimicrobial production of a vast and varied collection of Planctomycetes derived from marine macroalgae. Molecular analysis revealed that 95 percent of derived Planctomycetes contained one or both secondary bioactive genes: the NRPS and PKS genes. Moreover, the bioactivity assays revealed a large number of Planctomycetes (Planctomyces brasiliensis, Rhodopirellula lusitana, R. baltica, and R. rubra) with bioactive extracts that exhibited antibacterial and antifungal activities against B. subtilis and C. albicans, respectively [298] .

According to scientific evidence, around 2% of bacteria on Earth can be readily cultivated through a culture-dependent method [299] . There are presently 61 different bacterial phyla identified, 31 of which have no cultivable representatives. Thus, most bacteria are uncultivable and, therefore, the conventional culture techniques always underestimate the richness of diverse bacterial communities [300] . As a result of the development of certain culture-independent methods, there has been a shift toward the characterization of mixed bacterial communities within marine environmental biomass. However, several advanced molecular techniques should be developed for isolating the bacteria from marine environments, which may open new avenues to discovering more structurally unique and effective antimicrobial compounds. The genome study, functional gene screening, and gene manipulation of marine bacteria reveal the potential for producing a wide variety of novel antimicrobial compounds [301] [302] [303] . However, only a tiny percentage of the bacterial genes were expressed under certain cultivation states [304] . As a result, distinctive methods should be taken to activate the gene transcription and metabolic reprogramming efficiently. The extraction and characterization of bioactive compounds from marine bacteria are challenging since they are produced in small amounts and often mixed forms [67] . As a result, metabolic engineering may need to integrate with natural product drug research for the large-scale manufacturing of the bioactive compounds in marine bacteria.

Finally, we attempted to examine the trends in scientific publications during the past twenty-five years (1996-2020) in countries engaged in identifying marine bacteria for their antimicrobial potentials. Scientific output in this area has increased rapidly, with the Asian continent leading the way. Moreover, the research organizations in China, India, the USA, South Korea, and Germany have become the top five significant prospectors in identifying antimicrobial-producing marine bacteria ( Figure 15 ). It is clearly shown that the increasing focus of several countries on the identification of structurally unique and effective antimicrobial compounds from marine bacteria may indicate that a large number of new molecules may emerge as possible antimicrobial therapy options in the near future. Figure 15 . Statistical publication list from top ten countries engaged in studying marine bacteria for their antimicrobial activities. The data were retrieved from the PubMed database (https://pubmed.ncbi.nlm.nih.gov/, accessed on 25 July 2021) by providing the keywords "marine bacteria" and "antimicrobial activity" for the study period (1996-2020).

Overall, developing novel antimicrobial agents, and the alteration of existing drugs obtained from marine bacteria, will be crucial in fighting against microbial resistance. Considering all of the findings and technological advancements made over the past two and half decades, it is evident that marine bacteria will play a crucial role in the future development and trials of structurally unique and effective antimicrobial medicines.

Author Contributions: R.S. and X.L. conceived the concept of the review; R.S. and A.K. drafted the manuscript; R.S. prepared the figures and tables; R.S., A.K., C.S. and X.L. coordinated the work and acquired funding; R.S, A.K. and X.L. reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript. 

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Composition, uniqueness and variability of the epiphytic bacterial community of the green alga Ulva australis

De Clerck, O. Permanent residents or temporary lodgers: Characterizing intracellular bacterial communities in the siphonous green alga Bryopsis

Chemistry, biosynthesis and biological activity of terpenoids and meroterpenoids in bacteria and fungi isolated from different marine habitats

Cyclic tetrapeptides from marine bacteria associated with the seaweed Diginea sp. and the sponge Halisarca ectofibrosa

Isolation and structure elucidation of a novel yellow pigment from the marine bacterium Pseudoalteromonas tunicata

Inhibition of fungal colonization by Pseudoalteromonas tunicata provides a competitive advantage during surface colonization

Magnesidin, a novel magnesium-containing antibiotic

In vitro anti-methicillin-resistant Staphylococcus aureus activity of 2, 4-diacetylphloroglucinol produced by Pseudomonas sp. AMSN isolated from a marine alga

A newly isolated Pseudomonas sp., epibiotic on the seaweed, Padina tetrastromatica, off Southeastern Coast of India, reveals antibacterial action

New anticancer antibiotics pelagiomicins, produced by a new marine bacterium Pelagiobacter variabilis

Extinction risk assessment of the world's seagrass species

Protecting the hand that feeds us: Seagrass (Zostera marina) serves as commercial juvenile fish habitat

A comparative evaluation of biological activities and bioactive compounds of the seagrasses Zostera marina and Zostera noltei from southern Portugal

Conk Dalay, M. The essentials of marine biotechnology. Front

Diversity and antagonistic potential of bacteria isolated from marine grass Halodule uninervis

Diversity of culturable epiphytic bacteria isolated from seagrass (Halodule uninervis) in Thailand and their preliminary antibacterial activity

Mangroves of Orissa Coast: Floral diversity and conservation status. Spec. Habit. Threaten. Plants India ENVIS Wild Life Protect

A review on frequently occurring fungi in mangroves

Actinomycetes for marine drug discovery isolated from mangrove soils and plants in China

Actinomycetes of an Indian Mangrove (Pitchavaram) Environment; an Inventory

Antibacterial and antifungal activity of streptomycetes from Porto Novo coastal environment

The occurrence of bioactive micromonosporae in aquatic habitats of the Sunshine Coast in Australia

Micromonospora rifamycinica sp. nov., a novel actinomycete from mangrove sediment

A new degraded sesquiterpene from marine actinomycete Streptomyces sp. 0616208

Identification of Streptomyces sp-MWS1 producing antibacterial compounds

Phylogenetic analysis and antimicrobial activities of Streptomyces isolates from mangrove sediment

Antimicrobial compounds produced by Lysinibacillus odysseyi epiphytic bacteria associated with red algae

Identification of Asparagopsis armata-associated bacteria and characterization of their bioactive potential

Antimicrobial potential of epiphytic bacteria associated with seaweeds of Little Andaman

Desertomycin G, a new antibiotic with activity against Mycobacterium tuberculosis and human breast tumor cell lines produced by Streptomyces althioticus MSM3, isolated from the Cantabrian Sea Intertidal macroalgae Ulva sp

Antibacterial aryl-crowned polyketide from Bacillus subtilis associated with seaweed Anthophycus longifolius

Isolation, purification, structural elucidation and antimicrobial activities of kocumarin, a novel antibiotic isolated from actinobacterium Kocuria marina CMG S2 associated with the brown seaweed Pelvetia canaliculata

Previously undescribed antibacterial polyketides from heterotrophic Bacillus amyloliquefaciens associated with seaweed Padina gymnospora

Antimicrobial polyketide furanoterpenoids from seaweed-associated heterotrophic bacterium Bacillus subtilis MTCC 10403

O-heterocyclic derivatives with antibacterial properties from marine bacterium Bacillus subtilis associated with seaweed, Sargassum myriocystum

Antibacterial polyketides from Bacillus amyloliquefaciens associated with edible red seaweed Laurenciae papillosa

Antimicrobial properties of cultivable bacteria associated with seaweeds in the Gulf of Mannar on the southeast coast of India

Antimicrobial activities of bacteria associated with the brown alga Padina pavonica

Polyketide family of novel antibacterial 7-O-methyl-5 -hydroxy-3 -heptenoatemacrolactin from seaweed-associated Bacillus subtilis MTCC 10403

Recovery and characterization of a 30.7-kDa protein from Bacillus licheniformis associated with inhibitory activity against methicillin-resistant Staphylococcus aureus, vancomycinresistant Enterococci, and Listeria monocytogenes

Screening of antibacterial activity of seagrass-associated bacteria from the North Java Sea, Indonesia against multidrug-resistant bacteria

Bioactive potential of seagrass bacteria against human bacterial pathogens

Screening, partial purification of antivibriosis metabolite sterol-glycosides from Rhodococcus sp. against aquaculture associated pathogens

Azhar, E. Isolation, diversity, and biotechnological potential of rhizo-and endophytic bacteria associated with mangrove plants from Saudi Arabia

Purification, characterization and production optimization of a vibriocin produced by mangrove associated Vibrio parahaemolyticus

The current status of natural products from marine fungi and their potential as anti-infective agents

Natural products and the gene cluster revolution

Recent advances in awakening silent biosynthetic gene clusters and linking orphan clusters to natural products in microorganisms

Bioprospecting sponge-associated marine Cyanobacteria to produce bioactive compounds

Planctomycetes as novel source of bioactive molecules

Unculturable bacteria-The uncharacterized organisms that cause oral infections

Strategies for culture of 'unculturable'bacteria

Methods for the genetic manipulation of marine bacteria

Abd Elrazak, A. Targeted metagenomics as a tool to tap into marine natural product diversity for the discovery and production of drug candidates

Metagenomics approaches in discovery and development of new bioactive compounds from marine actinomycetes

Activation and identification of five clusters for secondary metabolites in Streptomyces albus J 1074