Basic mechanisms of bacterial tolerance of antimicrobial agents.

Although it has been known for many years that beta-lactam antibiotics inhibit the synthesis of peptidoglycan, it was the phenomenon of tolerance which allowed elucidation of the mode of action of beta-lactam antibiotics particularly with respect to the lysis of the bacteria. By studying tolerant pneumococci it was shown that penicillin triggers the production of autolytic enzymes which degrade the peptidoglycan to such an extent that lysis and killing of cells occurs. Since this discovery many studies have shown that various microorganisms are capable of preventing the lysis and/or killing action of beta-lactams. In Staphylococcus aureus strains, for instance, tolerance appears to be due to the lower specific activity of autolytic enzymes, extracted after exposure to a high concentration of methicillin (64 micrograms/ml). At these high concentrations of beta-lactams the same strains also show inhibition of RNA and protein synthesis. This inhibition of macromolecular synthesis is probably due to a feed-back mechanism which synchronizes synthesis rates of protein, RNA, peptidoglycan and the activity of autolytic enzymes.