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dc.contributor.authorMacsics, Robert
dc.contributor.authorHackl, Mathias W
dc.contributor.authorFetzer, Christian
dc.contributor.authorMostert, Dietrich
dc.contributor.authorBender, Jennifer
dc.contributor.authorLayer, Franziska
dc.contributor.authorSieber, Stephan A
dc.date.accessioned2020-09-11T12:22:32Z
dc.date.available2020-09-11T12:22:32Z
dc.date.issued2020-08-03
dc.identifier.pmid32503913
dc.identifier.doi10.1128/AEM.00933-20
dc.identifier.urihttp://hdl.handle.net/10033/622441
dc.description.abstractTriclocarban (TCC), a formerly used disinfectant, kills bacteria via an 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 show here that, like PK150, TCC exhibits an inhibitory effect on Staphylococcus aureus menaquinone metabolism via inhibition of the biosynthesis protein demethylmenaquinone methyltransferase (MenG). However, the activity spectrum (MIC90) of TCC across a broad range of multidrug-resistant staphylococcus and enterococcus strains was much narrower than that of PK150. Accordingly, TCC did not cause an overactivation 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 profiles 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 for an effect on bacterial energy metabolism by TCC.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. 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 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. 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.en_US
dc.language.isoenen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectStaphylococcus aureusen_US
dc.subjectantimicrobial agentsen_US
dc.subjectmechanisms of actionen_US
dc.subjectproteomicsen_US
dc.subjecttriclocarbanen_US
dc.subjecttriclosanen_US
dc.titleComparative Target Analysis of Chlorinated Biphenyl Antimicrobials Highlights MenG as a Molecular Target of Triclocarban.en_US
dc.typeArticleen_US
dc.identifier.eissn1098-5336
dc.contributor.departmentHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.en_US
dc.identifier.journalApplied and environmental microbiologyen_US
dc.source.volume86
dc.source.issue16
dc.source.journaltitleApplied and environmental microbiology
dc.source.countryUnited States


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