THE ENZYMIC BASIS OF SPECIFIC ANTIBACTERIAL ACTION BY STRUCTURAL ANALOGUES

Summary 1. The mechanism of action of structural analogues is examined to discover the extent to which their properties make them effective antibacterial agents in vivo. 2. Two main types of structural analogue may be recognized. First, there is the type which competes with a natural metabolite for a recognition site on the surface of a protein. Secondly, there are a few examples–notably cycloserine, and possibly penicillin–which inhibit non‐competitively by reacting covalently with an enzyme to inhibit its action. In general, inhibitors which react covalently are more effective in vivo than those which inhibit competitively. 3. Analogues which inhibit competitively act in three main ways: they may compete at the active centre of a single enzyme, or exert a ‘false feedback’ inhibition of the endogenous supply of an essential metabolite, or repress the formation of enzymes necessary for the biosynthesis of an essential metabolite. 4. Although structural analogues which inhibit competitively in one of these three ways can cause temporary inhibition in the growth of bacterial cells, their bacteriocidal effect is low, since resistant bacterial populations readily emerge. 5. Resistance to structural analogues which inhibit competitively at the active centre of a single enzyme may occur physiologically by the accumulation of the precursor to the inhibited enzyme. 6. Resistance to structural analogues which inhibit competitively may also occur by mutation. In the case of analogues acting at the active centres of enzymes, mutation may lead to resistance by lowering the affinity of the relevant enzyme for the analogue. Resistance to structural analogues acting as ‘false feedback’ inhibitors occurs when a mutation causes the synthesis of an enzyme with a lowered affinity for the structural analogue as a feedback inhibitor. Similarly, organisms resistant to the action of analogues as repressors are probably the result of a mutation which lowers the affinity of the ‘genetic repressor’ for the analogue in its role as the ‘low molecular weight repressor’. 7. Inhibitors which react covalently with an enzyme have certain advantages not found with analogues which act competitively, and these are discussed in relation to the mode of action of the cholinesterase inhibitor, di‐iso‐propylfluorophosphate. One advantage of this type of inhibitor is that reversal by the normal enzyme substrate does not readily occur. Secondly, this type of inhibitor is active at appreciably lower concentrations than simple competitive inhibitors. 8. The antibacterial action of cycloserine and penicillin are examined to see to what extent they are examples of structural analogues which react covalently with essential enzymes. 9. The fact that analogues which react covalently with enzymes are more effective inhibitors than analogues which act competitively, suggests that some form of covalent reaction may often be involved in the action of antibiotic substances.