Triclocarban (TCC), a formerly used disinfectant, kills bacteria viaan unknown mechanism of action. A structural hallmark is its N,N'-diaryl urea motif which is also present in other antibiotics including the recently reported small molecule PK150. We here show that, like PK150, TCC exhibits an inhibitory effect on Staphylococcus aureus menaquinone metabolism via inhibition of the biosynthesis protein MenG. However, the activity spectrum (MIC90) of TCC across a broad range of multi-drug resistant staphylococci and enterococci strains was much narrower compared to PK150. Accordingly, TCC did not cause an over-activation of signal peptidase SpsB, a hallmark of the PK150 mode of action. Furthermore, we were able to rule out inhibition of FabI, a confirmed target of the diaryl ether antibiotic triclosan (TCS). Differences in the target profile of TCC and TCS were further investigated by proteomic analysis, showing complex, but rather distinct changes in the protein expression profile of S. aureus. Downregulation of the arginine deiminase pathway provided additional evidence foran effect on bacterial energy metabolism by TCC.
Macsics, R*., Hackl, M. W., Fetzer C., Mostert, D., Bender, J., Layer, F., Sieber, S. A., "Comparative Target Analysis of Chlorinated Biphenyl Antimicrobials Highlights MenG as Molecular Target of Triclocarban", Appl. Environ. Microbiol.,