Genetic and pharmacological inactivation of peptidoglycan remodeling increases antibiotic susceptibility of vancomycin-resistant Enterococcus faecium

Fam, Kyong T, Chodisetti, Pavan Kumar, Wang, Zifei, Homer, Joshua A, Smedley, Christopher J, Kitamura, Seiya, Silva, Benjamin, Xiong, Yijun, Hansel-Harris, Althea, Holcomb, Matthew, Babarinde, Simeon, Turner, Adrianna M, Van Tyne, Daria, Wilson, Ian A, Forli, Stefano, Cravatt, Benjamin F, Park, Donghyun, Wolan, Dennis W, Moses, John E, Hang, Howard C (March 2026) Genetic and pharmacological inactivation of peptidoglycan remodeling increases antibiotic susceptibility of vancomycin-resistant Enterococcus faecium. bioRxiv. ISSN 2692-8205 (Submitted)

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Abstract

Vancomycin-resistant Enterococcus faecium (VREfm) is a leading cause of healthcare-associated infections globally and demands new approaches for treatment. Here we show that genetic and pharmacological inactivation of a highly conserved NlpC/P60 peptidoglycan hydrolase, secreted antigen A (SagA), enhanced vancomycin susceptibility of VREfm ex vivo and in vivo. Notably, genetic deletion of sagA impaired VREfm peptidoglycan remodeling, growth and increased the activity of vancomycin. We then identified first-in-class covalent NlpC/P60 peptidoglycan hydrolase inhibitors and demonstrated that pharmacological inactivation of SagA activity also impaired peptidoglycan remodeling and increased the efficacy of vancomycin across genetically distinct VREfm clinical isolates. Our study reveals peptidoglycan hydrolases are druggable targets whose inactivation improves the efficacy of vancomycin against VREfm.

Item Type: Paper
Subjects: diseases & disorders > Bacterial Infections
diseases & disorders
CSHL Authors:
Communities: CSHL labs > Moses lab
CSHL Post Doctoral Fellows
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 11 March 2026
Date Deposited: 01 Apr 2026 12:28
Last Modified: 01 Apr 2026 12:28
PMCID: PMC13014144
Related URLs:
URI: https://repository.cshl.edu/id/eprint/42139

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