Drug repurposing of some US FDA-approved drugs using Binding strength Studies for the Treatment of Methicillin-resistant Staphylococcus aureus Infection

Methicillin-resistant Staphylococcus aureus (MRSA) is a major multidrug-resistant bacterial pathogen responsible for severe infections worldwide. The increasing resistance of MRSA to conventional antibiotics has created an urgent need for new therapeutic strategies. Drug repurposing of US FDA-approved drugs offers a promising approach to identify alternative anti-MRSA agents while reducing the time and cost associated with traditional drug discovery. In this study, computational Binding strength analysis was performed to evaluate the inhibitory potential of selected compounds against important MRSA target enzymes, including thioredoxin reductase 1, proton motive force protein, and penicillin-binding protein 2a (PBP2a). Molecular docking results demonstrated strong interactions between the ligands and the active sites of the selected enzymes. The native ligand NL_3QFB showed the strongest Binding strength toward thioredoxin reductase 1 with a docking score of −12.2 kcal/mol, while the reference drug Auranofin exhibited −7.8 kcal/mol. For the proton motive force protein, NL_9U6O displayed a docking score of −7.4 kcal/mol, comparable to Niclosamide (−7.5 kcal/mol). Similarly, NL_6Q9N showed strong interaction with PBP2a with a docking score of −8.6 kcal/mol, whereas Afamelanotide showed weaker binding (−1.9 kcal/mol). ADMET analysis indicated acceptable physicochemical and pharmacokinetic properties for several compounds. Overall, the findings suggest that the investigated ligands demonstrate promising Binding capability and favorable drug-like properties against MRSA target enzymes. However, further experimental validation is required to confirm their therapeutic potential.

1. 01.

   1. Enright MC, Robinson DA, Randle G, Feil EJ, Grundmann H, Spratt BG. The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA). Proc Natl Acad Sci U S A. 2002;99(11):7687–92. doi: 10.1073/pnas.122108599.

   DOI: 10.1073/pnas.122108599 Google Scholar
2. 02.

   2. Harkins CP, Pichon B, Doumith M, Parkhill J, Westh H, Tomasz A, et al. Methicillin-resistant Staphylococcus aureus emerged long before the introduction of methicillin into clinical practice. Genome Biol. 2017;18(1):130. doi: 10.1186/s13059-017-1252-9.

   DOI: 10.1186/s13059-017-1252-9 Google Scholar
3. 03.

   3. Binek M, Kizerwetter-Świda M, Rzewuska M, Chrobak-Chmiel D, Sałamaszyńska-Guz A. Antibiotic Resistance Of Bacteria A Growing Threat For Animals And Public Health. Postępy Mikrobiol - Adv Microbiol. 2019;58(3):259–70. doi: 10.21307/PM-2019.58.3.259.

   DOI: 10.21307/PM-2019.58.3.259 Google Scholar
4. 04.

   4. Goetghebeur M, Landry PA, Han D, Vicente C. Methicillin-resistant Staphylococcus aureus: A public health issue with economic consequences. Can J Infect Dis Med Microbiol. 2007;18(1):27–34. doi: 10.1155/2007/253947.

   DOI: 10.1155/2007/253947 Google Scholar
5. 05.

   5. Soares Magalhães RJ, Loeffler A, Lindsay J, Rich M, Roberts L, Smith H, et al. Risk factors for methicillin-resistant Staphylococcus aureus (MRSA) infection in dogs and cats: A case-control study. Vet Res. 2010;41(5). doi: 10.1051/vetres/2010028.

   DOI: 10.1051/vetres/2010028 Google Scholar
6. 06.

   6. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52(3):e18-55. doi: 10.1093/cid/ciq146.

   DOI: 10.1093/cid/ciq146 Google Scholar
7. 07.

   7. Li Y, Ma H. Drug repurposing: insights into the antimicrobial effects of AKBA against MRSA. AMB Express. 2024;14(1):5. doi: 10.1186/s13568-024-01660-0.

   DOI: 10.1186/s13568-024-01660-0 Google Scholar
8. 08.

   8. Li Y, She P, Liu Y, Guo S, Huang G, Xiao D, et al. Drug Repurposing: An Emerging Strategy in Staphylococcus aureus Infections. J Microbiol Biotechnol. 2025;35(10):e2507048. doi: 10.4014/jmb.2507.07048.

   DOI: 10.4014/jmb.2507.07048 Google Scholar
9. 09.

   9. Wielders CLC, Fluit AC, Brisse S, Verhoef J, Schmitz FJ. mecA gene is widely disseminated in Staphylococcus aureus population. J Clin Microbiol. 2002;40(11):3970–5. DOI: 10.1128/JCM.40.11.3970-3975.2002.

   DOI: 10.1128/JCM.40.11.3970-3975.2002 Google Scholar
10. 10.

    10. Vieira G, Leal N, Rodrigues A, Chaves C, Rodrigues F, Osório N. MRSA/MSSA causing infections: prevalence of mecA gene. Eur J Public Health. 2020;30(Supplement_2). doi: 10.1093/eurpub/ckaa040.052.

    DOI: 10.1093/eurpub/ckaa040.052 Google Scholar
11. 11.

    11. Villegas-Estrada A, Lee M, Hesek D, Vakulenko SB, Mobashery S. Co-opting the cell wall in fighting methicillin-resistant Staphylococcus aureus: Potent inhibition of PBP 2a by two anti-MRSA β-Lactam Antibiotics. J Am Chem Soc. 2008;130(29):9212–3. doi: 10.1021/ja8029448.

    DOI: 10.1021/ja8029448 Google Scholar
12. 12.

    12. Foster TJ. Can β-Lactam Antibiotics Be Resurrected to Combat MRSA? Vol. 27, Trends in Microbiology. 2019. p. 26–38. doi: 10.1016/j.tim.2018.06.005.

    DOI: 10.1016/j.tim.2018.06.005 Google Scholar
13. 13.

    13. Vestergaard M, Frees D, Ingmer H. Antibiotic Resistance and the MRSA Problem. Microbiol Spectr. 2019;7(2). doi: 10.1128/microbiolspec.gpp3-0057-2018.

    DOI: 10.1128/microbiolspec.gpp3-0057-2018 Google Scholar
14. 14.

    14. Dancer SJ. The effect of antibiotics on methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother. 2008;61(2):246–53. doi: 10.1093/jac/dkm465.

    DOI: 10.1093/jac/dkm465 Google Scholar
15. 15.

    15. Eckmann C, Dryden M. Treatment of complicated skin and soft-tissue infections caused by resistant bacteria: Value of linezolid, tigecycline, daptomycin and vancomycin. Eur J Med Res. 2010;15(12):554–63. doi: 10.1186/2047-783x-15-12-554.

    DOI: 10.1186/2047-783x-15-12-554 Google Scholar
16. 16.

    16. Estes KS, Derendorf H. Comparison of the pharmacokinetic properties of vancomycin, linezolid, tigecyclin, and daptomycin. Eur J Med Res. 2010;15(12):533–43. doi: 10.1186/2047-783x-15-12-533.

    DOI: 10.1186/2047-783x-15-12-533 Google Scholar
17. 17.

    17. Canut A, Isla A, Gascón AR, Betriu C, Gascón AR. Pharmacokinetic-pharmacodynamic evaluation of daptomycin, tigecycline, and linezolid versus vancomycin for the treatment of MRSA infections in four western European countries. Eur J Clin Microbiol Infect Dis. 2012;31(9):2227–35. doi: 10.1007/s10096-012-1560-7.

    DOI: 10.1007/s10096-012-1560-7 Google Scholar
18. 18.

    18. Sharma R, Gupta V, Parashar B, Chawla V, Chawla PA. Resilience Against Resistance: Exploring Cutting-edge Therapies for Methicillin-resistant Staphylococcus aureus (MRSA). Curr Med Chem. 2024;32(41):9324–43. 10.2174/0109298673316661241002060518.

    Google Scholar
19. 19.

    19. Gopikrishnan M, Haryini S, George Priya Doss C. Emerging strategies and therapeutic innovations for combating drug resistance in Staphylococcus aureus strains: A comprehensive review. Vol. 64, Journal of Basic Microbiology. 2024;64(5):e2300579. doi: 10.1002/jobm.202300579.

    DOI: 10.1002/jobm.202300579 Google Scholar
20. 20.

    20. Abebe AA, Birhanu AG. Methicillin Resistant Staphylococcus aureus: Molecular Mechanisms Underlying Drug Resistance Development and Novel Strategies to Combat. Vol. 16, Infection and Drug Resistance. 2023. p. 7641–62. doi: 10.2147/idr.s428103.

    DOI: 10.2147/idr.s428103 Google Scholar
21. 21.

    21. Tomoda H. New approaches to drug discovery for combating MRSA. Chem Pharm Bull. 2016;64(2):104–11. doi: 10.1248/cpb.c15-00743.

    DOI: 10.1248/cpb.c15-00743 Google Scholar
22. 22.

    22. Siddiqui Q, Shaikh YA. Hydroalcoholic Extraction of Cissus quadrangularis and In Vitro Evaluation of Antifungal Properties. J PharmTechNova. 2026;01(01):3–10. doi: 10.66220/vyc7rc95.

    DOI: 10.66220/vyc7rc95 Google Scholar
23. 23.

    23. Siddiqui FS. Computational Assessment of Secondary Metabolites as Potential Inhibitors of Methylenetetrahydrofolate Dehydrogenase-2 ( MTHFD2 ). J Phytopharm Adv Chem. 2026;01(01):3–17. doi: 10.66220/wwze8340.

    DOI: 10.66220/wwze8340 Google Scholar
24. 24.

    24. Gandla K, Islam F, Zehravi M, Karunakaran A, Sharma I, Haque MA, et al. Natural polymers as potential P-glycoprotein inhibitors: Pre-ADMET profile and computational analysis as a proof of concept to fight multidrug resistance in cancer. Heliyon. 2023;9(9). doi: 10.1016/j.heliyon.2023.e19454.

    DOI: 10.1016/j.heliyon.2023.e19454 Google Scholar
25. 25.

    25. Jadhav PB, Jadhav SB, Zehravi M, Mubarak MS, Islam F, Jeandet P, et al. Virtual Screening, Synthesis, and Biological Evaluation of Some Carbohydrazide Derivatives as Potential DPP-IV Inhibitors. Molecules. 2023;28(1). doi: 10.3390/molecules28010149.

    DOI: 10.3390/molecules28010149 Google Scholar
26. 26.

    26. Suryawanshi RM, Shimpi RB, Muralidharan V, Nemade LS, Gurugubelli S, Baig S, et al. ADME, Toxicity, Molecular Docking, Molecular Dynamics, Glucokinase activation, DPP-IV, α-amylase, and α-glucosidase Inhibition Assays of Mangiferin and Friedelin for Antidiabetic Potential. Chem Biodivers. 2025;22(5). doi: 10.1002/cbdv.202402738.

    DOI: 10.1002/cbdv.202402738 Google Scholar