Proteomics

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

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 in several VREfm clinical isolates. Our study reveals peptidoglycan hydrolases are druggable targets whose inactivation improves the efficacy of vancomycin against VREfm.

INSTRUMENT(S):

ORGANISM(S): Enterococcus Faecium Erv165

SUBMITTER: Kyong Fam  

LAB HEAD: Howard C. Hang

PROVIDER: PXD075040 | Pride | 2026-04-13

REPOSITORIES: pride

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20231009_SoL_ERV165_YX_pghi-4.txt Txt
20231009_SoL_ERV165_YX_pghi-4_01.raw Raw
20231009_SoL_ERV165_YX_pghi-4_02.raw Raw
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Genetic and pharmacological inactivation of peptidoglycan remodeling increases antibiotic susceptibility of vancomycin-resistant <i>Enterococcus faecium</i>.

Fam Kyong T KT   Chodisetti Pavan Kumar PK   Wang Zifei Z   Homer Joshua A JA   Smedley Christopher J CJ   Kitamura Seiya S   Silva Benjamin B   Xiong Yijun Y   Hansel-Harris Althea A   Holcomb Matthew M   Babarinde Simeon S   Turner Adrianna M AM   Van Tyne Daria D   Wilson Ian A IA   Forli Stefano S   Cravatt Benjamin F BF   Park Donghyun D   Wolan Dennis W DW   Moses John E JE   Hang Howard C HC  

bioRxiv : the preprint server for biology 20260311

Vancomycin-resistant <i>Enterococcus faecium</i> (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 <i>ex vivo</i> and <i>in vivo</i>. Notably, genetic deletion of <i>sagA</i> impaired VREfm peptidoglycan remodeling, growth and increased the activity  ...[more]

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