Recently, we published the development of a novel antibacterial compound named PK150, which was derived from the anticancer drug sorafenib (SFN) ( Fig. However, a specific protein target as in the case of TCS has not been identified so far. Finally, a study which aimed at generating improved derivatives of TCC investigated the mode of action by fluorescence staining and microscopy and found TCC to induce cell lysis and membrane deformation ( 22). Comparison of TCC and TCS by molecular dynamics simulations, though, suggested that at high concentrations both compounds might destabilize the lipid bilayer membrane in a similar nonspecific manner ( 21). While TCS is known to inhibit enoyl-acyl-carrier-protein reductase FabI ( 16, – 18) and has been proposed to further disturb the lipid bilayer nonspecifically at higher concentrations ( 19), the corresponding mechanisms for TCC are rather unclear, and studies into their elucidation are scarce one study investigated the production of membrane leakage by several compounds but found no such effect for TCC ( 20). In contrast to the very extensive studies on its impact on health and environment, surprisingly little is known about the antibacterial mode of action of TCC. aureus NCTC 8325 are displayed below the respective structures.
![vac ban remover 2018 mw2 vac ban remover 2018 mw2](https://i.gyazo.com/277024e76fdb2cf8623f1c2b8cef1df9.png)
![vac ban remover 2018 mw2 vac ban remover 2018 mw2](https://pics.me.me/thumb_when-vou-qget-accidental-back-to-back-headshots-through-a-wall-and-55357888.png)
Structures of the antibacterial agents triclocarban (TCC) and triclosan (TCS), structurally related PK150, and sorafenib (SFN). Adding to these health-related concerns are environmental problems due to their multiple chlorination sites, these compounds are persistent to biodegradation and were thus shown to accumulate in the environment and cause potentially toxic effects in soil and water organisms ( 10, – 15).
![vac ban remover 2018 mw2 vac ban remover 2018 mw2](https://img.youtube.com/vi/AptLg1ZVQBM/0.jpg)
TCS, in contrast, was demonstrated to depolarize the inner mitochondrial membrane and uncouple oxidative phosphorylation ( 7, – 9). TCC and TCS can be absorbed by the body ( 2, 3) and were found to exhibit several mammalian off-target effects both act as weak endocrine disruptors ( 4), and TCC was additionally found to exhibit anti-inflammatory effects by inhibiting soluble epoxide hydrolase and to alter cardiac function by interference with fatty acid metabolism in mouse models ( 3, 5, 6). In 2017, however, the Food and Drug Administration (FDA) banned the use of TCC together with that of triclosan (TCS), another halogenated biphenyl antimicrobial agent ( Fig. Triclocarban (TCC) is a broad-spectrum anti-infective agent that has been used in personal care products such as soaps and lotions since the 1960s ( 1). The prevailing differences, however, which also manifest in a remarkably better broad-spectrum activity of PK150, suggest that even high levels of TCC or TCS resistance observed by continuous environmental exposure may not affect the potential of PK150 or related N, N′-diaryl urea compounds as new antibiotic drug candidates against multidrug-resistant infections. We show that there are distinct differences in each compound’s mode of action, but also identify a shared target between TCC and PK150, the interference with menaquinone metabolism by inhibition of MenG. With its antibacterial mechanism of action still being unknown, we undertook a comparative target analysis between TCC, PK150 (a recently discovered antibacterial compound with structural resemblance to TCC), and TCS (another widely employed chlorinated biphenyl antimicrobial) in the bacterium Staphylococcus aureus. IMPORTANCE TCC’s widespread use as an antimicrobial agent has made it a ubiquitous environmental pollutant despite its withdrawal due to ecological and toxicological concerns. Downregulation of the arginine deiminase pathway provided additional evidence for an effect on bacterial energy metabolism by TCC. Differences in the target profiles of TCC and TCS were further investigated by proteomic analysis, showing complex but rather distinct changes in the protein expression profile of S. Furthermore, we were able to rule out inhibition of FabI, a confirmed target of the diaryl ether antibiotic triclosan (TCS). Accordingly, TCC did not cause an overactivation of signal peptidase SpsB, a hallmark of the PK150 mode of action. However, the activity spectrum (MIC 90) of TCC across a broad range of multidrug-resistant staphylococcus and enterococcus strains was much narrower than that of PK150. We show here that, like PK150, TCC exhibits an inhibitory effect on Staphylococcus aureus menaquinone metabolism via inhibition of the biosynthesis protein demethylmenaquinone methyltransferase (MenG). A structural hallmark is its N, N′-diaryl urea motif, which is also present in other antibiotics, including the recently reported small molecule PK150.
![vac ban remover 2018 mw2 vac ban remover 2018 mw2](https://cdn.mos.cms.futurecdn.net/8qp8CfV2ab8jmo2FjqRLZn.jpg)
Triclocarban (TCC), a formerly used disinfectant, kills bacteria via an unknown mechanism of action.