Fighting Antimicrobial Resistance: Insights on How the Staphylococcus aureus NorA Efflux Pump Recognizes 2-Phenylquinoline Inhibitors by Supervised Molecular Dynamics (SuMD) and Molecular Docking Simulations

The superbug Staphylococcus aureus (S.aureus) exhibits several resistance mechanisms, includingefflux pumps, that strongly contribute to antimicrobial resistance.In particular, the NorA efflux pump activity is associated with S. aureus resistance to fluoroquinolone antibiotics (e.g., ciprofloxacin) by promoting their active extrusionfrom cells. Thus, since efflux pump inhibitors (EPIs) are able toincrease antibiotic concentrations in bacteria as well as restoretheir susceptibility to these agents, they represent a promising strategyto counteract bacterial resistance. Additionally, the very recentrelease of two NorA efflux pump cryo-electron microscopy (cryo-EM)structures in complex with synthetic antigen-binding fragments (Fabs)represents a real breakthrough in the study of S. aureus antibiotic resistance. In this scenario, supervised molecular dynamics(SuMD) and molecular docking experiments were combined to investigatefor the first time the molecular mechanisms driving the interactionbetween NorA and efflux pump inhibitors (EPIs), with the ultimategoal of elucidating how the NorA efflux pump recognizes its inhibitors.The findings provide insights into the dynamic NorA-EPI intermolecularinteractions and lay the groundwork for future drug discovery effortsaimed at the identification of novel molecules to fight antimicrobialresistance.