Regulatory interactions between daptomycin and bacitracin responsive pathways coordinate the cell envelope antibiotic resistance response of Enterococcus faecalis

Sali M. Morris, Laura Wiens, Olivia Rose, Georg Fritz, Tim Rogers, Susanne Gebhard

Research output: Contribution to journalArticlepeer-review

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. To better understand the regulation of DAP resistance and how this relates to mutations observed in DAP-resistant clinical isolates of enterococci, we here explored the interplay between these two regulatory pathways. Our results show that SapR regulates an additional resistance operon, dltXABCD, a known DAP resistance determinant, and show that LiaFSR regulates the expression of sapRS. This regulatory structure places SapRS-target genes under dual control, where expression is directly controlled by SapRS, which itself is up-regulated through LiaFSR. The network structure described here shows how Enterococcus faecalis coordinates its response to cell envelope attack and can explain why clinical DAP resistance often emerges via mutations in regulatory components.
Original languageEnglish
JournalMolecular Microbiology
Early online date22 Apr 2024
DOIs
Publication statusE-pub ahead of print - 22 Apr 2024

Data Availability Statement

The data that support the findings of this study are available in the supplementary material. The numerical data underpinning the results shown in Figures 1– 4 are available in Table S4. The Mathematica file for the model is provided in the supplementary material as File S1.

Keywords

  • antimicrobial peptides
  • antimicrobial resistance
  • cell envelope stress
  • signalling
  • two-component system

ASJC Scopus subject areas

  • Molecular Biology
  • Microbiology

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