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Triclocarban vs Triclosan: A look into the protein targets of chlorinated biphenyl antimicrobials

ABSTRACT: Triclocarban (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. Like PK150, TCC exhibited a similar inhibitory effect on menaquinone metabolism via inhibition of the biosynthesis protein MenG, suggesting a contribution of this pathway to its mode of action. However, the activity spectrum (MIC90) of TCC across a broad range of resistant staphylococci and enterococci strains was much narrower compared to PK150. Accordingly, TCC did not cause an overactivation of signal peptidase SpsB, a hallmark of the PK150 scaffold. 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 the bacteria. Additional evidence for an effect on bacterial energy metabolism was provided for TCC. Taken together, this study shows that N,N'-diaryl urea motifs exhibit shared and distinct molecular targets and for the first time highlights MenG as a target of TCC.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Robert Macsics

LAB HEAD: Stephan Axel Sieber

PROVIDER: PXD018347 | Pride | 2020-06-04

REPOSITORIES: Pride

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Project description:Aiming at the development of a micropollutant biosensor in the frame of the Micro-Ecological Life Support System Alternative (MELiSSA), a pilot study was initiated to identify triclosan (TCS)-responsive biomarker genes in the MELiSSA carbon-mineralizing microorganism, Rhodospirillum rubrum S1H. TCS is a biocide, commonly found in human excrements and is considered an emerging pollutant in wastewater and the environment. Chronic exposure to MELiSSA-relevant concentrations (≥25 µg L-1) TCS caused a significant extension of the lag phase without affecting the growth rate. Analytical determination gave no indication of TCS biodegradation during the growth experiment and flow cytometric viability analyses revealed that TCS is only slightly toxic to R. rubrum. Through microarray analyses, the genetic mechanisms supporting the reversibility of TCS-induced inhibition were scrutinized. Hence, an extremely TCS-responsive cluster of four small adjacent genes was revealed, with up to 34-fold induction at 25 µg L-1. These four genes, for which the name micropollutant-upregulated factor (muf) was proposed; appear to be unique to R. rubrum and are shown for the first time to be involved in the response to stress. Moreover, numerous other systems that are associated with the proton-motive force were shown to be responsive to TCS, but never as highly upregulated as the muf genes. Hence, R. rubrum induced the phage shock protein operon (pspABC), numerous major facilitator efflux systems, cell envelope consolidation mechanisms, oxidative stress response, beta-oxidation, and carbonic anhydrase; while downregulating bacterial conjugation- and carboxysome synthesis genes. The muf genes and three efflux-related genes showed most potential as low-dose biomarkers. The two microarray experiments (10 and 25 µg l-1 Triclosan) were all performed in biological triplicate and containing three (in-slide) technical repeats. For all conditions, the Triclosan exposed sample (Cy5) was compared with the non-exposed solvent control (Cy3) to identify those genes that were differentially expressed upon Triclosan exposure.

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Triclocarban vs Triclosan: A look into the protein targets of chlorinated biphenyl antimicrobials

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