Virtual Toxicity Screening and Molecular Docking of Natural Compounds to Discover New Antibiotics for MethicillinResistant Staphylococcus aureus

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a strain whose resistance against existing antibiotics is a serious threat to life. MRSA causes mild skin infections, invasive infections, newborn infections, and surgical patient infections that can lead to death. MRSA quickly develops resistance to new treatments, contributing to the global antimicrobial resistance pandemic. In Uganda, MRSA is now resistant to commonly used antibiotics like ceftriaxone, cefixime, levofloxacin, ciprofloxacin, and chloramphenicol, thus a need to explore new antibiotics to treat diseases caused by MRSA. Its resistance against these drugs continues to worry the health sector, given that in the past two decades, very few drugs successfully entered the market. This is because the well-known traditional experimental drug development and testing process is lengthy and slow and requires huge investments. In this study, we performed virtual screening to discover potential compounds that have antibacterial activity against MRSA. We conducted an extensive literature search and found 180 compounds with antibacterial activity against MRSA. On further screening, only 21 out of 180 compounds were common in Uganda. Thereafter, we conducted both virtual toxicity and molecular docking on the identified 21 compounds. PES12 had score values below the acceptable physicochemical properties considered for toxicity analysis. The molecular docking analysis between the interaction of 21compounds with two macromolecular targets of MRSA, namely, nitrocefin acyl-Penicillin binding protein 2a (1MWS) and SeMet Penicillin binding protein 2a (1MWR), showed binding energy ranging from −2.7 and −18.6 kcal/mol. Compound PES01 has an excellent binding affinity value of −18.6 kcal/mol, which is far greater than that of known drugs (−6.9 to 8.7 kcal/mol) for treating infection due to MRSA. This study’s findings could inform the development of new and more potential antibiotics; however, there is a need to conduct animal studies and clinical trials to understand the effectiveness of the identified 21 compounds.

Received: 29 April 2025 | Revised: 23 June 2025 | Accepted: 22 July 2025

Conflicts of Interest

The authors declare that there are no conflicts of interest with this study.

Data Availability Statement

The data that support the findings of this study are openly available in Ressource Parisienne en BioInformatique Structurale (RPBS) at https://bioserv.rpbs.univ-paris-diderot.fr/services.html; PreADMET at https://preadmet.qsarhub.com/.

Author Contribution

Simon Kawuma: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization, Project administration. David Sabiiti Bamutura: Methodology, Software, Data curation, Writing – original draft, Writing – review & editing, Visualization. Izath Nura: Investigation, Writing – original draft, Writing – review & editing. Daniel Zziwa Ashiraf: Investigation, Writing – original draft, Writing – review & editing. Joel Bazira: Methodology, Validation, Resources, Writing – original draft, Writing – review & editing, Supervision, Project administration, Funding acquisition.