Novel regulatory logic in the antibiotic resistance response of Enterococcus faecalis against cell envelope targeting antibiotics

Sali M. Morris, Georg Fritz, Tim Rogers, Susanne Gebhard

Research output: Working paperPreprint

Abstract

Enterococcal infections frequently show high levels of antibiotic resistance, including to cell envelope-acting antibiotics like daptomycin (DAP). While we have a good understanding of the resistance mechanisms, less is known about the control of such resistance genes in enterococci. Previous work unveiled a bacitracin resistance network, comprised of the sensory ABC transporter SapAB, the two-component system (TCS) SapRS and the resistance ABC transporter RapAB. Interestingly, components of this system have recently been implicated in DAP resistance, a role usually regulated by the TCS LiaFSR. We here explored the interplay between these two regulatory pathways. Our results show the regulation by SapR of an additional resistance operon, dltXABCD, and show that LiaFSR regulates the expression of sapRS, placing SapRS target genes under dual control: dltXABCD expression depends on both antibiotic-induced cellular damage (LiaFSR) and the presence of a substrate drug for the sensory transporter (SapAB). We further show that this network protects E. faecalis from antimicrobials produced by potential competitor bacteria, providing a potential rationale for the evolution of this regulatory strategy. The network structure described here can explain why clinical DAP resistance often emerges via mutations in regulatory components, which may ultimately lead to the discovery of new therapeutic targets.
Original languageEnglish
PublisherbioRxiv
DOIs
Publication statusSubmitted - Nov 2022

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