The molecular basis for the mode of action of beta-lactam antibiotics and mechanisms of resistance

This review on the molecular basis for the mode of action of β-lactam antibiotics and mechanisms of resistance is divided into three main sections. Firstly, a brief introduction to the β-lactam antibiotic family is presented from the standpoint of their natural product origins. The second section is concerned with bacterial cell wall structure and biosynthesis, and the mode of action of β-lactam antibiotics. It includes an attempted rationalization of the multiple enzyme targets of penicillin, the so-called "penicillin binding proteins", into one or two lethal sites of action and the interaction of these enzymes with β-lactams in terms of their analogy to the natural substrate and to the substrate-enzyme transition state. The final part covers the phenomenon of bacterial resistance to β-lactam antibiotic therapy and deals with the two most important manifestations of resistance; permeability and the production of β-lactamases. This latter more crucial factor is then expanded with particular reference to the irreversible inhibition of these enzymes by suicide inactivators; a general theory for irreversible β-lactamase inhibition is discussed and the future prospects within this whole area are briefly overviewed.