Bacitracin sensing and resistance in Staphylococcus aureus

Abstract

Bacterial two-component systems (TCSs) have been demonstrated to be associated with not only the expression of virulence factors, but also the susceptibility to antibacterial agents. In Staphylococcus aureus, 16 types of TCSs have been identified. We previously found that the inactivation of one uncharacterized TCS (designated as BceRS, MW gene ID: MW2545-2544) resulted in an increase in susceptibility to bacitracin. In this study, we focused on this TCS and tried to identify the TCS-controlled factors affecting the susceptibility to bacitracin. We found that two ABC transporters were associated with the susceptibility to bacitracin. One transporter designated as BceAB (MW2543-2542) is downstream of this TCS, while another (formerly designated as VraDE: MW2620-2621) is separate from this TCS. Both transporters showed homology with several bacitracin-resistance factors in Gram-positive bacteria. Inactivation of each of these two transporters increased the susceptibility to bacitracin. Expressions of these transporters were significantly increased by the addition of bacitracin, while this induction was not observed in the TCS-inactivated mutant. These results indicate that this TCS senses bacitracin, and also positively regulates the expression of two ABC transporters.

Coevolution of ABC Transporters and Two-Component Regulatory Systems as Resistance Modules against Antimicrobial Peptides in Firmicutes Bacteria

“…The second group IV transporter is VraDE (Table 3, Ͼ229), whose expression is partially controlled by GraRS (34), again matching our prediction. However, expression of vraDE is also dependent on the TCS NsaRS, as was shown recently in a study on bacitracin resistance of S. aureus (54). Mutants in nsaRS (named bceRS in the cited study), mw2543-2542, or vraDE all displayed increased sensitivity to bacitracin (54), thus indicating the existence of a more complex regulatory network: while it appears clear that NsaRS regulates the expression of both transporters (54), it has not been shown if both also mediate the actual resistance or if one transporter merely contributes to the signaling cascade.…”

“…However, expression of vraDE is also dependent on the TCS NsaRS, as was shown recently in a study on bacitracin resistance of S. aureus (54). Mutants in nsaRS (named bceRS in the cited study), mw2543-2542, or vraDE all displayed increased sensitivity to bacitracin (54), thus indicating the existence of a more complex regulatory network: while it appears clear that NsaRS regulates the expression of both transporters (54), it has not been shown if both also mediate the actual resistance or if one transporter merely contributes to the signaling cascade. According to our classification, such a regulatory interaction with the HK would be possible only for the MW2543-2542 transporter, which belongs to the same phylogenetic group as NsaS (Fig.…”

Lantibiotic Resistance

“…A BceRS-like (IM-HK) TCS associated with S. aureus, BraRS, has been shown to be essential for resistance to bacitracin, nisin, and nukacin ISK-1 (108,(122)(123)(124). As a consequence of having been identified in three separate studies, this TCS is also referred to as BceRS (123) and NsaRS (125). The name BraRS (bacitracin resistance associated) is representative of its characteristics and thus has been chosen for further referral (108).…”

Further Insights into the Mode of Action of the Lipoglycopeptide Telavancin through Global Gene Expression Studies

“…VraDE comprise an ABC transporter involved in antimicrobial peptide detoxification (40,43). The system is induced by various antimicrobial peptides, including bacitracin, nisin, mersacidin, indolicidin, ovisporin-1-NH 2 , temporin-1-NH 2 , dermaseptin, K4-S4 (1-16)-NH 2 , vancomycin, and teicoplanin (13,16,27,40,43,53). To this list we can add telavancin and enduracidin as strong inducers.…”