Drug repurposing enhances antibiotic activity in multidrug-resistant staphylococcus aureus through modulation of oxidative stress homeostasis
4 affiliations
- 1Faculty of Medical Sciences, UM6P Hospitals, Mohammed VI Polytechnic University
- 2Algal Biotechnology Center, Moroccan Foundation for Advanced Science, Innovation, and Research (MAScIR), Mohammed VI Polytechnic University
- 3Chemical and Biochemical Sciences Department, Mohammed VI Polytechnic University
- 4Laboratoire de Biochimie et Génétique Moléculaire, Faculté des Sciences et Techniques de Tanger
Abstract
Introduction: Antimicrobial resistance represents a major therapeutic challenge, particularly in Staphylococcus aureus , and highlights the urgent need for alternative strategies to enhance the efficacy of existing antibiotics. Modulating bacterial stress-response pathways, especially the RecA-mediated SOS response, may provide a promising adjuvant approach to increase bacterial susceptibility to antibiotic-induced stress.
Methods: This study investigated the potential of repurposed FDA-approved drugs to act as antibiotic adjuvants following in silico identification of compounds predicted to interact with the bacterial recombinase RecA. An integrated workflow was applied, combining in silico screening, formulation selection and optimization, biochemical validation, and in vitro antibacterial assays. The selected formulation was evaluated alone and in combination with streptomycin using IC ₅₀ determination, oxidative stress assessment, RecA-associated ATPase activity measurement, growth curve, and colony-forming unit enumeration.
Results: Among the tested formulations, the selected combination enhanced streptomycin activity against resistant S. aureus , leading to a 2.2-fold reduction in IC ₅₀ while showing no marked antibacterial effect when used alone. These findings support its role as an antibiotic adjuvant rather than as a directly active antibacterial treatment. Mechanistic investigation suggested that the potentiation of streptomycin activity was associated with increased oxidative stress and reduced RecA-associated ATPase activity. The improved antibacterial performance of the combination treatment was further confirmed by growth kinetics analysis and colony-forming unit enumeration.
Conclusion: These findings suggest that targeting RecA can increase bacterial susceptibility to antibiotic-induced stress and enhance streptomycin efficacy against resistant S. aureus . This study supports the development of stress-response-targeted antibiotic adjuvant strategies as a promising approach to improve the therapeutic performance of existing antibiotics.
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BibTeX
@article{chagra2026drug,
title = {{Drug repurposing enhances antibiotic activity in multidrug-resistant staphylococcus aureus through modulation of oxidative stress homeostasis}},
author = {Zaineb Chagra and Wessal Ouedrhiri and Salma Loukman and Sara El Asri and Rachid El Fatimy and Reda Ben Mrid},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1873160},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1873160/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Drug repurposing enhances antibiotic activity in multidrug-resistant staphylococcus aureus through modulation of oxidative stress homeostasis
AU - Zaineb Chagra
AU - Wessal Ouedrhiri
AU - Salma Loukman
AU - Sara El Asri
AU - Rachid El Fatimy
AU - Reda Ben Mrid
PY - 2026
DA - 2026/10/19
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1873160
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1873160/full
AB - Introduction: Antimicrobial resistance represents a major therapeutic challenge, particularly in Staphylococcus aureus , and highlights the urgent need for alternative strategies to enhance the efficacy of existing antibiotics. Modulating bacterial stress-response pathways, especially the RecA-mediated SOS response, may provide a promising adjuvant approach to increase bacterial susceptibility to antibiotic-induced stress. Methods: This study investigated the potential of repurposed FDA-approved drugs to act as antibiotic adjuvants following in silico identification of compounds predicted to interact with the bacterial recombinase RecA. An integrated workflow was applied, combining in silico screening, formulation selection and optimization, biochemical validation, and in vitro antibacterial assays. The selected formulation was evaluated alone and in combination with streptomycin using IC ₅₀ determination, oxidative stress assessment, RecA-associated ATPase activity measurement, growth curve, and colony-forming unit enumeration. Results: Among the tested formulations, the selected combination enhanced streptomycin activity against resistant S. aureus , leading to a 2.2-fold reduction in IC ₅₀ while showing no marked antibacterial effect when used alone. These findings support its role as an antibiotic adjuvant rather than as a directly active antibacterial treatment. Mechanistic investigation suggested that the potentiation of streptomycin activity was associated with increased oxidative stress and reduced RecA-associated ATPase activity. The improved antibacterial performance of the combination treatment was further confirmed by growth kinetics analysis and colony-forming unit enumeration. Conclusion: These findings suggest that targeting RecA can increase bacterial susceptibility to antibiotic-induced stress and enhance streptomycin efficacy against resistant S. aureus . This study supports the development of stress-response-targeted antibiotic adjuvant strategies as a promising approach to improve the therapeutic performance of existing antibiotics.
SN - 1663-9812
ER -