Investigating the bispecific lead compounds against methicillin-resistant Staphylococcus aureus SarA and CrtM using machine learning and molecular dynamics approach

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a notorious pathogen that has emerged as a serious global health concern over the past few decades. Staphylococcal accessory regulator A (SarA) and 4,4′-diapophytoene synthase (CrtM) play a crucial role in biofilm formation and staphyloxanthin biosynthesis. Thus, the present study used a machine learning-based QSAR model to screen 1261 plant-derived natural organic compounds in order to identify a medication candidate with both biofilm and virulence inhibitory potential. Additionally, the in-silico molecular docking analysis has demonstrated significant binding efficacy of the identified hit compound, that is 85137543, with SarA and CrtM when compared to the control compound, hesperidin. Post-MD simulation analysis of the complexes depicted strong binding of 85137543 to both SarA and CrtM. Moreover, 85137543 showed hydrogen bonding with the key residues of both proteins during docking (ALA138 of SarA and ALA134 of CrtM) and post-MD simulation (LYS273 of CrtM and ASN212 of SarA). The RMSD of 85137543 was stable and consistent when bound to both CrtM and SarA with RMSDs of 1.3 and 1 nm, respectively. In addition, principal component analysis and the free energy landscape showed stable complex formation with both proteins. Low binding free energy (ΔGTotal) was observed by 85137543 for SarA (−47.92 kcal/mol) and CrtM (−36.43 kcal/mol), which showed strong binding. Overall, this study identified 85137543 as a potential inhibitor of both SarA and CrtM in MRSA.

Communicated by Ramaswamy H. Sarma

Keywords:

• Methicillin-resistant
• Staphylococcus aureus
• SarA (Staphylococcal accessory regulator A)
• CrtM (4
• 4′-diapophytoene synthase)
• plant-derived natural organic compounds

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research has been funded by Deputy for Research & Innovation, Ministry of Education through Initiative of Institutional Funding at University of Ha’il—Saudi Arabia through project number IFP-22178.