Genetic and pharmacological inactivation of peptidoglycan remodeling increases antibiotic susceptibility of vancomycin-resistant Enterococcus faecium
Year: 2026
Type: article
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.
Source: Nature Communications
Authors: Kyong T. Fam, Pavan Kumar Chodisetti, Zifei Wang, Joshua A. Homer, Christopher J. Smedley, Seiya Kitamura, Benjamin Silva, Yijun Xiong, Althea Hansel-Harris, Matthew Holcomb, Simeon Babarinde, Adrianna M. Turner, Daria Van Tyne, Ian A. Wilson, Stefano Forli, Benjamin F. Cravatt, Donghyun Park, Dennis W. Wolan, John E. Moses, Howard C. Hang
Language: English
Subfield: Molecular Medicine
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1509738654, Developing next generation click chemistry, Modulation of host immunity with recombinant peptidoglycan hydrolases, High-speed direct detector for cryo electron microscopy, G4161720544, G4373432326, G9000279778, Adaptation of vancomycin-resistant enterococci during bloodstream infection, AutoDock Suite: High Performance Software Environment for Drug Design, CSHL Cancer Center Support Grant
OpenAlex ID: W4414258708