Antibiotics affecting bacterial wall synthesis

Abstract

The initial observations on the effect of benzylpenicillin on the bacterial wall came in the early 1940s shortly after its introduction as a therapeutic agent. Gardner [74] found that concentrations of penicillin, much lower than those required to kill a range of different bacteria, caused considerable morphological changes to the organisms with apparent damage to the cell envelope. In certain organisms, cell division also appeared inhibited. These observations were extended by Duguid [58] who showed that growth was a necessary requirement for penicillin action, and that killing of the bacteria was apparently associated with cell lysis. He suggested that ‘penicillin at these concentrations interferes specifically with the formation of the outer cell wall, while otherwise allowing growth to proceed until the organism finally bursts its defective envelope and undergoes cell lysis’. Many Gram-positive bacteria, particularly staphylococci, are extremely sensitive to the inhibitory action of penicillin, suggesting that its action is highly specific. This observation prompted the first biochemical studies of Park and Johnson [208] who described the accumulation of a labile phosphate compound by Staphylococcus aureus when treated with penicillin. The accumulated material was subsequently shown to be composed of several nucleotide compounds, all of which contained an unknown amino sugar, and some, the uncommon D-isomers of glutamic acid and alanine too [201–203] ; the function of these compounds was not known. However, when it was discovered the wall of S. aureus contained a structure analogous to part of the accumulated nucleotidepeptide, it became clear that the compounds were in fact the biosynthetic precursors of the wall [209]. At this time, considerable advances were being made in the determination of bacterial wall structure, many of which pointed to its being unique. These findings, taken in conjunction with the other studies on the mode of action of penicillin, pointed to the wall as a structure necessary for the survival of the organism and in consequence a site for the selective action of antibiotics. The biosynthesis of peptidoglycan has been discussed in detail in the previous chapter and a number of antibiotics have been mentioned where information relating to biosynthesis has resulted from investigation of their mode of action. The mode of action of these and other antibiotics will now be described in greater detail at a molecular level. This consideration will be related to their site of action in the synthesis of peptidoglycan, which may be at the level of synthesis of the nucleotide precursors, the membrane-bound stages involving the lipid carrier or the terminal stages involving transfer of the newly-synthesized unit to the growing peptidoglycan.