Ertapenem Exposure Is Associated with Downregulation of Purine Biosynthesis Proteins and Inhibition of Biofilm Formation in Staphylococcus aureus
- 1All India Institute of Medical Sciences , ,
- 2Bennett University , , ,
Abstract
Staphylococcus aureus is a major cause of both nosocomial and community-acquired infections, imposing a significant burden on healthcare systems owing to its capacity for mature biofilm formation. These biofilms create polymer-based matrices that reduce bacterial vulnerability to immune responses and antimicrobial agents, complicating the treatment of drug-resistant S. aureus strains and underscoring the need for novel antibacterial targets. Here, we provide the first evidence that FGAM synthase (PurQ), an essential enzyme in the de novo purine biosynthesis pathway, is a putative intracellular protein target associated with ertapenem exposure in S. aureus. Our study demonstrates that ertapenem exhibits potent antibacterial activity against S. aureus (MIC = 1 μg/mL) and is a potential inhibitor of biofilm formation. Mechanistically, this antibiofilm activity correlates with selective downregulation of purine biosynthesis proteins. Using LC-MS/MS analysis of biofilm-derived adherent S. aureus cells, we quantified 1,706 proteins and identified 59 proteins with statistically significant expression changes in ertapenem-treated versus untreated S. aureus cells (49 downregulated, 10 upregulated). Proteins associated with purine biosynthesis were predominantly downregulated, particularly FGAM synthase (PurQ) with a −2.29 log2 fold change. Molecular docking supported by 100 ns molecular dynamics simulations demonstrated stable ertapenem binding to the PurQ active site (docking score: −9.615 kcal/mol) through interactions with key residues: Gly53, Asp54, Tyr55, Gln89, His141, Gly142, Glu143, and Gly144. Collectively, these findings implicate a novel aspect of ertapenem’s activity, connected to the disruption of purine biosynthesis in S. aureus through targeted downregulation of FGAM synthase. This work provides a strong foundation for drug repurposing strategies aimed at targeting purine biosynthesis in drug-resistant bacterial pathogens.
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BibTeX
@article{singh2026ertapenem,
title = {{Ertapenem Exposure Is Associated with Downregulation of Purine Biosynthesis Proteins and Inhibition of Biofilm Formation in Staphylococcus aureus}},
author = {Anamika Singh and Surabhi Pandit and Pradeep Pant and Tej P. Singh and Sujata Sharma and Pradeep Sharma},
journal = {ACS omega},
year = {2026},
month = oct,
doi = {10.1021/acsomega.5c11260},
url = {https://europepmc.org/article/PMC/PMC13670320},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Ertapenem Exposure Is Associated with Downregulation of Purine Biosynthesis Proteins and Inhibition of Biofilm Formation in Staphylococcus aureus
AU - Anamika Singh
AU - Surabhi Pandit
AU - Pradeep Pant
AU - Tej P. Singh
AU - Sujata Sharma
AU - Pradeep Sharma
PY - 2026
DA - 2026/10/01
JO - ACS omega
DO - 10.1021/acsomega.5c11260
UR - https://europepmc.org/article/PMC/PMC13670320
AB - Staphylococcus aureus is a major cause of both nosocomial and community-acquired infections, imposing a significant burden on healthcare systems owing to its capacity for mature biofilm formation. These biofilms create polymer-based matrices that reduce bacterial vulnerability to immune responses and antimicrobial agents, complicating the treatment of drug-resistant S. aureus strains and underscoring the need for novel antibacterial targets. Here, we provide the first evidence that FGAM synthase (PurQ), an essential enzyme in the de novo purine biosynthesis pathway, is a putative intracellular protein target associated with ertapenem exposure in S. aureus. Our study demonstrates that ertapenem exhibits potent antibacterial activity against S. aureus (MIC = 1 μg/mL) and is a potential inhibitor of biofilm formation. Mechanistically, this antibiofilm activity correlates with selective downregulation of purine biosynthesis proteins. Using LC-MS/MS analysis of biofilm-derived adherent S. aureus cells, we quantified 1,706 proteins and identified 59 proteins with statistically significant expression changes in ertapenem-treated versus untreated S. aureus cells (49 downregulated, 10 upregulated). Proteins associated with purine biosynthesis were predominantly downregulated, particularly FGAM synthase (PurQ) with a −2.29 log2 fold change. Molecular docking supported by 100 ns molecular dynamics simulations demonstrated stable ertapenem binding to the PurQ active site (docking score: −9.615 kcal/mol) through interactions with key residues: Gly53, Asp54, Tyr55, Gln89, His141, Gly142, Glu143, and Gly144. Collectively, these findings implicate a novel aspect of ertapenem’s activity, connected to the disruption of purine biosynthesis in S. aureus through targeted downregulation of FGAM synthase. This work provides a strong foundation for drug repurposing strategies aimed at targeting purine biosynthesis in drug-resistant bacterial pathogens.
SN - 2470-1343
ER -