Beta-lactams in the new millennium. Part-I: monobactams and carbapenems.

Beta-lactam ring-containing compounds such as penicillins, ampicillin, amoxicillin, cephalosporins and carbapenem are among the most famous antibiotics. This article reviews the recent developments in the study of such compounds. The introductory paragraph, which highlights the significance of the subject and cites most of the leading references of the previous century, is followed by an overview of beta-lactams and some novel methodologies for the synthesis of bi-, tri- and polycyclic derivatives. The rest of the sections deal with design, synthesis and biological activity of monobactams and carbapenems. Many of them have potential antibacterial activity, even against some resistant strains, and enzyme inhibitory activity.

MM 42842, a new member of the monobactam family produced by Pseudomonas cocovenenans. II. Production, isolation and properties of MM 42842.

A new member of the monobactam family of beta-lactam antibiotics, designated MM 42842, has been detected in a culture of Pseudomonas cocovenenans. The production, isolation and some properties of the antibiotic are described. Structural studies show MM 42842 to be closely related to the previously described antibiotic sulfazecin.

PB-5266 A, B and C, new monobactams. I. Taxonomy, fermentation and isolation.

New monobactams, PB-5266 A, B and C were isolated from the culture filtrate of Cytophaga johnsonae PB-5266 by various types of column chromatography and preparative reverse phase HPLC. PB-5266 A, B and C exhibited weak antibacterial activity against a sensitive mutant of Escherichia coli to beta-lactam antibiotics.

Discovery and development of the monobactams.

A novel procedure designed to detect naturally occurring beta-lactam-containing molecules led to isolation of the monobactams - structurally unique, bacterially produced, monocyclic beta-lactam antibiotics. Although none of these monobactams exhibited impressive antimicrobial activity, side-chain variation - as with the penicillins and cephalosporins - resulted in potently active compounds. Aztreonam was chosen from hundreds of compounds for extended laboratory studies. In addition to a unique chemical structure, aztreonam has biologic properties that are unique in comparison with those of the classical penicillins and cephalosporins. Aztreonam is relatively inactive against gram-positive bacteria and anaerobes but is extremely effective against aerobic gram-negative bacteria, including Pseudomonas aeruginosa. The drug is highly resistant to enzymatic hydrolysis by beta-lactamases, particularly those known to be mediated by R plasmids, and is a poor inducer of chromosomal beta-lactamases. In the majority of drug combinations tested, aztreonam exhibits additive or synergistic activity. In a series of animal-model infections, the drug showed a high degree of efficacy that was consistent with findings in studies in vitro. In a hamster model for Clostridium difficile-induced pseudomembranous colitis, aztreonam did not induce any significant changes.