Effect of subminimal inhibitory concentrations of mecillinam on the synthesis of DNA, RNA, and protein of Salmonella typhimurium: a proposed mechanism of action.

Salmonellae alter their rod-like morphology to become large ovals within 3-5 hr after being exposed to concentrations of mecillinam below the minimal inhibitory concentration. Before this overt morphologic change occurs, synthesis of DNA increases, with a concomitant decrease in total protein synthesis. Incorporation of [3H]leucine into cell wall protein is markedly inhibited by mecillinam, whereas incorporation of leucine into soluble intracellular proteins is enchanced by the drug. Electrophoretic separation of stained, soluble intracellular proteins of salmonellae exposed to mecillinam indicates that as many as 15-20 individual groups of protein occur at higher concentrations in mecillinam-exposed salmonellae than in unexposed control organisms. These results suggest that, at low concentrations, mecillinam binds selectively to cell wall components, thereby interfering with the assembly of the cell wall during growth. This interference causes a buildup of newly synthesized soluble proteins that are normally involved in cell wall assembly. The weakening of the cell wall, combined with this buildup, causes the cell to assume a three-dimensional oval structure that is the result of equal hydrostatic pressure exerted by the medium.