Membrane Lipids Augment Cell Envelope Stress Signaling and Resistance to Antibiotics and Antimicrobial Peptides in Enterococcus faecalis

William R. Miller, April Nguyen, Kavindra V. Singh, Samie Rizvi, Ayesha Khan, Samuel G. Erickson, Stephanie Egge, Melissa R. Cruz, An Dinh, Lorena Diaz, Rutan Zhang, Libin Xu, Danielle A. Garsin, Yousif Shamoo, Cesar A. Arias

Research output: Contribution to journalArticle

Abstract

Enterococci have evolved resistance mechanisms to protect their cell envelopes against bacteriocins and host cationic antimicrobial peptides (CAMPs) produced in the gastrointestinal environment. Activation of the membrane stress response has also been tied to resistance to the lipopeptide antibiotic daptomycin. However, the actual effectors mediating resistance have not been elucidated. Here, we show that the MadRS (formerly YxdJK) membrane antimicrobial peptide defense system controls a network of genes, including a previously uncharacterized three gene operon (madEFG) that protects the E. faecalis cell envelope from antimicrobial peptides. Constitutive activation of the system confers protection against CAMPs and daptomycin in the absence of a functional LiaFSR system and leads to persistence of cardiac microlesions in vivo. Moreover, changes in the lipid cell membrane environment alter CAMP susceptibility and expression of the MadRS system. Thus, we provide a framework supporting a multilayered envelope defense mechanism for resistance and survival coupled to virulence.
Original languageEnglish (US)
Article numberVersion 2. bioRxiv. 2023 Oct 19. doi: 10.1101/2023.10.17.562839 PMCID: PMC10614854 PMID: 37904970
Pages (from-to)1 - 30
Number of pages30
JournalbioRxiv
StatePublished - Oct 19 2023

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