Chapter 13. β-Lactam Antibiotics

Abstract

This chapter discusses the recent studies and researches regarding β-lactum antibiotics. The focus of semisynthetic modifications in the β-lactam antibiotics has been directed toward derivatives having broad-spectrum activity with increased potency against both gram-positive organisms and pseudomonas or derivatives with improved pharmacokinetics. Several new analogs containing 7-heterocyclyl-α-oximino-acetamido side chains, having broad-spectrum activity and improved pharmacokinetics, have been discussed in the chapter. Penicillins and cephalosporins with 7α-substituents other than methoxy generally show reduced anti-bacterial activities. It is essentially devoid of activity against gram-positive bacteria comparing well both in vitro and in vivo with ceftazidime against pseudomonas species and with cefotaxime and aztreonam versus the Enterobacteriacae . Preliminary pharmacokinetic studies in man show it to be well tolerated and to exhibit a favorable pharmacokinetic profile. The synthesis, antibacterial activity, and β-lactamase stability of a group of 6-α-hydroxymethylpenicillins has been discussed in the chapter. The syntheses of 2-β-alanyloxymethyl, 2-glycyloxymethyl, and 2-methyl analogs of thienamycin have been described in this chapter. These analogs have showed only weak activity against P. aeruginosa though they displayed potent, broad-spectrum activity toward gram-positive and other gram-negative bacteria. Penicillanic acid sulfone appears to inhibit irreversibly the RTEM β-lactamase from E. coli by forming a crosslink within the enzyme. The crosslink is a β-aminoacrylaie fragment derived from C-5, C-6, and C-7 of the inhibitor. The progress made in the recent years in unraveling the biosynthetic pathway that converts the arnstein tripeptide, l-α-aminoadipyl-Lcysteinyl-D-valine (ACV) into penicillins and cephalosporins has opened a new avenue to synthesizing novel β-lactams. More recently, four pathway enzymes from Streptomyces clavuligerus have been immobilized on an ion-exchange resin and, in the presence of appropriate cofactors, selected tripeptides have been converted into modified penicillins or cephalosporins.