How penicillin kills bacteria: progress and problems

Abstract

Penicillins and cephalosporins are specific inhibitors of the biosynthesis of bacterial cell walls. This discovery was first made in 1957 and was based on two observations. First, penicillins induced the formation of protoplasts or spheroplasts in bacteria (organisms in which the cell wall has been lost or weakened) (Lederberg 1957). Secondly, a uridine nucleotide accumulated in Staphylococcus aureus and other bacteria inhibited by penicillin which had a striking relationship to the composition of the cell wall (Park & Strominger 1957). It was therefore suggested that this nucleotide was an activated precursor of the wall. Over the next decade, a great deal of work was carried out in order to elucidate the structure of the bacterial cell wall and the mechanism of its biosynthesis from the uridine nucleotides and other precursors (reviewed by Strominger 1970; Strominger & Ghuysen 1967; Ghuysen 1968). It was demonstrated that interpeptide cross-links were an important structural feature of the wall. Several kinds of experiments carried out with whole cells indicated that the final step in cell wall synthesis, the crosslinking reaction catalysed by a transpeptidase, was the site of action of penicillin (Wise & Park 1965; Tipper & Strominger 1965 a , b , 1968). Finally, in 1966, the transpeptidase catalysing this cross-linking reaction was obtained in a cell-free system and shown to be a penicillin-sensitive enzyme (Izaki, Matsuhashi & Strominger 1966, 1968). The history of these developments has been reviewed elsewhere (Strominger 1970), and in the present paper, attention will be focused on recent studies of the penicillin-sensitive transpeptidase and other penicillinsensitive activities found in bacterial cell membranes. First, however, it is necessary to describe briefly the structure of the cell wall of bacteria and the nature of the inhibited reactions. The walls of bacteria consist of glycan strands in which two sugars, acetylglucosamine (X) and acetylmuramic acid (Y), strictly alternate (figure 1). Four such glycan strands are represented in figure 1. The acetylmuramic acid residues of the polymer are substituted by a tetrapeptide (represented in the figure by open circles). The peptidoglycan strand (i.e., the glycan substituted by the tetrapeptide) are cross-linked to one another by means of an interpeptide bridge which is to some extent a genus-specific character­istic. In the genus Staphylococcus aureus , the interpeptide bridge is a pentaglycine chain (represented in figure 1 by the closed circles) which extends from the carboxyl group on the terminal D-alanine residue of the tetrapeptide to the ∊-amino group of lysine, the third amino acid in the tetrapeptide chain. The wall of S . aureus is a very tightly knit structure in that virtually every peptide subunit is cross-linked to another subunit by means of this interpeptide bridge. Penicillins and cephalosporins are specific inhibitors of the reaction in which the cross-link is actually formed. This step is the last reaction in wall synthesis.