Abstract

-Lactam antibiotics are one of the best established classes of antimicrobial agents for the treatment of infectious diseases. By screening strains of bacteria that were specifically responsive to -lactam antibiotics, monocyclic -lactams, ie, monobactams, varying in substitution at the C-3 position, were identified. The naturally occurring monobactams include SQ 26,180 (), SQ 26,445 (C₁₂H₂₀N₄O₉S), sulfazecin (C₁₂H₂₀N₄O₉S), and isosulfazecin (C₁₂H₂₀N₄O₉S). More recently, the 4-methyl analogue of SQ 26,445/sulfazecin was isolated using a differential antibacterial assay. Initial syntheses employed the sulfonation of an N-1 unsubstituted azetidinone as the key step. The natural product SQ, 26,180 as well as other methoxylated monobactams were synthesized. Subsequently, many more C-3 side-chain analogues were prepared. A second, distinct chiral synthesis of monobactams was developed from -hydroxy amino acids. The methodology was also applied to the synthesis of 4- and 4-methyl monobactams. The monobactams, like penicillins and cephalosporins, interfere with the synthesis of bacterial cell walls. B-Lactam antibiotics bind to a series of penicillin-binding proteins (PBPs) on the cytoplasmic membrane and their antibacterial effect is believed to result from inhibition of a subset of these PBPs known as peptidoglycan transpeptidases. Although naturally occurring monobactams have exhibited poor antibacterial activity, alteration of the C-3 amide side chain has led to many potent new compounds. Aztreonam is a totally synthetic compound that exhibits potent and specific activity against a wide range of both -lactamase-producing and nonproducing aerobic gram-negative bacteria, including Pseudomonas aeruginosa, but displays minimal inhibition against anaerobic and gram-positive aerobic bacteria, eg, staphylococci and streptococci. Two monobactams were in clinical use as of 1990. Aztreonam, manufactured by Bristol-Myers Squibb, has the worldwide trademark of Azactam. Carumonam, manufactured by Takeda in Japan, has the trademark Amasulin.