ABC-transporters with dual functions - detoxification and signalling by resistance modules against antimicrobial peptides

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A sensitive detection of the extracellular presence of antibiotics, coupled with an efficient means of signal transduction across the cell envelope, is a vital first step in mediating antimicrobial resistance. Recently, a unique group of modular systems, comprised of two-component regulatory systems (TCS) coupled to ATP-binding cassette transporters, has been identified in the response of low G+C Gram-positive bacteria to cell wall active peptide antibiotics. The best understood example for this mode of signal transduction is the BceRS-BceAB module of Bacillus subtilis, involved in bacitracin sensing and resistance. BceRS constitutes the TCS required for activation of the BceAB transporter, which in turn appears to act as an antibiotic pump. Strikingly, the transporter is also required for the detection of antimicrobial peptides by the sensor kinase BceS. Preliminary data suggest an unusual mode of signal transduction where the stimulus is detected by the transporter and communicated to the TCS via direct interactions between the transport permease and histidine kinase. The current proposal addresses central open questions regarding the molecular and biochemical mechanisms underpinning substrate binding, signal transduction and resistance by these self-sufficient detoxification modules.