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Updated: Jun 17, 2026

Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
11:56

Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection

Published on: October 25, 2013

Genetic and pharmacological inactivation of peptidoglycan remodeling increases antibiotic susceptibility of

Kyong T Fam1, Pavan Kumar Chodisetti1, Zifei Wang2

  • 1Department of Immunology and Microbiology, Scripps Research; La Jolla, CA, USA.

Nature Communications
|June 15, 2026
PubMed

Insights

Targeting the peptidoglycan hydrolase SagA enhances vancomycin effectiveness against vancomycin-resistant Enterococcus faecium (VREfm). Inactivating SagA improves VREfm treatment outcomes, offering new therapeutic strategies for these difficult-to-treat infections.

Area of Science:

  • Microbiology
  • Biochemistry
  • Drug Discovery

Background:

  • Vancomycin-resistant Enterococcus faecium (VREfm) poses a significant global health threat, driving the need for novel treatment strategies.
  • Current treatments are limited, necessitating research into alternative therapeutic targets and approaches to overcome resistance.

Purpose of the Study:

  • To investigate the role of the NlpC/P60 peptidoglycan hydrolase, secreted antigen A (SagA), in VREfm vancomycin resistance.
  • To explore SagA as a potential therapeutic target for enhancing vancomycin efficacy against VREfm.

Main Methods:

  • Genetic inactivation of the sagA gene in VREfm strains.
  • Pharmacological inhibition of SagA activity using novel covalent inhibitors.
  • Assessment of VREfm growth, peptidoglycan remodeling, and vancomycin susceptibility ex vivo and in vivo.

Main Results:

  • Genetic deletion of sagA impaired VREfm peptidoglycan remodeling and growth, increasing vancomycin susceptibility.
  • Pharmacological inhibition of SagA similarly disrupted peptidoglycan remodeling and enhanced vancomycin efficacy across diverse VREfm isolates.
  • Novel covalent inhibitors targeting NlpC/P60 peptidoglycan hydrolases were identified.

Conclusions:

  • Peptidoglycan hydrolases, specifically SagA, are druggable targets for combating VREfm infections.
  • Inactivation of SagA represents a promising strategy to resensitize VREfm to vancomycin, improving treatment outcomes.

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