title: Bacitracin and nisin resistance in Staphylococcus aureus: a novel pathway involving the BraS/BraR two-component system (SA2417/SA2418) and both the BraD/BraE and VraD/VraE ABC transporters.
abstract: Two-component systems (TCSs) are key regulatory pathways allowing bacteria to adapt their genetic expression to environmental changes. Bacitracin, a cyclic dodecylpeptide antibiotic, binds to undecaprenyl pyrophosphate, the lipid carrier for cell wall precursors, effectively inhibiting peptidoglycan biosynthesis. We have identified a novel and previously uncharacterized TCS in the major human pathogen Staphylococcus aureus that we show to be essential for bacitracin and nisin resistance: the BraS/BraR system (Bacitracin resistance associated; SA2417/SA2418). The braRS genes are located immediately upstream from genes encoding an ABC transporter, accordingly designated BraDE. We have shown that the BraSR/BraDE module is a key bacitracin and nisin resistance determinant in S. aureus. In the presence of low antibiotic concentrations, BraSR activate transcription of two operons encoding ABC transporters: braDE and vraDE. We identified a highly conserved imperfect palindromic sequence upstream from the braDE and vraDE promoter sequences, essential for their transcriptional activation by BraSR, suggesting it is the likely BraR binding site. We demonstrated that the two ABC transporters play distinct and original roles in antibiotic resistance: BraDE is involved in bacitracin sensing and signalling through BraSR, whereas VraDE acts specifically as a detoxification module and is sufficient to confer bacitracin and nisin resistance when produced on its own. We show that these processes require functional BraD and VraD nucleotide-binding domain proteins, and that the large extracellular loop of VraE confers its specificity in bacitracin resistance. This is the first example of a TCS associated with two ABC transporters playing separate roles in signal transduction and antibiotic resistance.
authors.affiliation: Institut Pasteur, Biology of Gram-Positive Pathogens, Department of Microbiology, 25 Rue du Docteur Roux, 75724 Paris Cedex 15, France.
authors.forename: Aurélia
authors.initials: A
authors.lastname: Hiron
authors.forename: Mélanie
authors.initials: M
authors.lastname: Falord
authors.forename: Jaione
authors.initials: J
authors.lastname: Valle
authors.forename: Michel
authors.initials: M
authors.lastname: Débarbouillé
authors.forename: Tarek
authors.initials: T
authors.lastname: Msadek
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000222:Adaptation, Physiological; D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D001414:Bacitracin / Q000378:metabolism* / Q000494:pharmacology; D001483:Base Sequence; D024881:Drug Resistance, Bacterial; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D008969:Molecular Sequence Data; D005810:Multigene Family; D009561:Nisin / Q000378:metabolism* / Q000494:pharmacology; D009876:Operon; D011401:Promoter Regions, Genetic; D016415:Sequence Alignment; D015398:Signal Transduction; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D023181:Antimicrobial Cationic Peptides; D001414:Bacitracin; D009561:Nisin