Novel and potentially 'universal' cephalosporins were designed as multifunctional β-lactam antibiotics which would be useful against both sensitive and resistant microorganisms. The three key structural variables that comprised this studies were the R group, the leaving group (LG), and R§ group. Different R§ and leaving groups were introduced based on their relative migratory aptitude or on their different leaving abilities, respectively. It was initially believed that some new ÌøåÀå_8ÌøåÀå_5-lactamase inhibitors could arise from this series of cephalosporins. Enzymatic processing of the ÌøåÀå_8ÌøåÀå_5-lactam may release a potent acylating agent called an isocyanate which can deactivate ÌøåÀå_8ÌøåÀå_5-lactamases irreversibly. Generation of this isocyanate can arise from appropriately substituted hydroxamates located at the C-3§ position of the cephalosporin through an intramolecular Lossen rearrangement after hydrolysis of the ÌøåÀå_8ÌøåÀå_5-lactam ring.,p>Several new C-3§-hydroxamate substituted cephalosporins were synthesized including cyclic forms 32-36, and 38 with improved lipophility and evaluated for antibacterial/anti-TB activity. The test results showed that the ring opened free carboxylic acid hydroxamates 27-31, and 37 are superior in activity compared to the corresponding cyclic hydroxamate esters 32-36, and 38 against some specific strains such as Micrococcus luteus ATCC 10240, Bacillus subtilis 6633 and S. aureus SG 511. The preliminary results showed electron donating groups gave better anti-TB activity (33 with an MIC of 2.81 ÌøåÀå_0ÌøåÀå_8M against GAST NRP-TB). This preliminary study provides exciting leads to the possible generation of compounds that are selective antimicrobial agents based on variation of peripheral substituents. To further test this concept, the synthesis of an extended library will be needed.In addition, the direct amine-linked quinolone-cephem 74 and carbamate-linked quinolone-cephem 77, and their corresponding esters 73 and 76 were synthesized and evaluated for anti-bacterial activity. All conjugates and their esters showed good activity against various strains of bacteria. Conjugate 74, the amine-linked quinolone-cephalosporin, was more active against some Gram-negative bacteria, while the carbamate-linked conjugate 77 had superior antimycobacterial/anti-TB activity with an MIC of 0.94 ÌøåÀå_0ÌøåÀå_8M.