Chapter 13. β-Lactam Antibiotics

Abstract

This chapter presents observations from the various reviews published on β-Lactam Antibiotics. There is discussion on cephalosporins, penicillins, penems, carbapenems, monocyclic β-lactams, β-lactamase inhibitors, biosynthetic pathways, and enzymes. A major concern in the clinical application of the β-lactam antibiotics continues to be the development of resistance to these antibiotics particularly by pseudomonas and enterobacter species. The first examples of 7-α-methoxycephem antibiotics to be isolated from bacteria, were the cephabacins M. The unique structural feature of these cephems, such as the cephabacins F and H, is the presence of an oligopeptide side chain at the 3-position. These antibiotics exhibit weak antibacterial activity with properties between those of the cephabacins F and H. A number of new parenteral cephalosporins were reported with improved in vitro activity against pseudomonas species. Commonly these antipseudomonal compounds were characterized by the presence of a quaternary ammonium function at the 3-position along with an aminothiazolyloximino grouping in the 7-acyl side chain. Extensive SAR studies on a series of 3-isoindolinium cephalosporins led to the selection of BO-1232 and BO-1236. The latter compounds were about ten times more active than ceftazidime against aeruginosa and more active against other pseudomonads as well. Another series of 3’-quaternary ammonium cephalosporins, the heterocyclic groups were pyridothiazoles, pyridoimidazoles, pyridooxazoles, and thiazoles. Many of these derivatives displayed potent antipseudomonal activity. Comparison of the antimicrobial properties of temocillin sidechain epimers revealed that the R-isomer is twice as potent as the S-isomer against aeruginosa, however; epimerization takes place rapidly even under normal bioassay conditions. One study showed that the β-methyl of penicillin N labeled from the chiral methyl of valine suffered complete epimerization in the oxidative ring expansion to deacetoxycephalosporin C. The conversion of the latter to deacetylcephalosporin C in acremonium strictum was shown to proceed with retention of configuration.