Synthesis and in Silico Pharmacokinetics of Some Sulfone Functionalized Thioproline Appended α/γ Hybrid Peptides as Potential Inhibitors of NorA Efflux Pump in Staphylococcus aureus

Staphylococcus aureus is a severe pathogenic agent accountable for a variety of disease conditions from soft tissue and skin infections to life-threatening endocarditis, pneumonia, and sepsis. Its disease load is multiplied by the fast emergence of multidrug resistance due to membrane-bound efflux pumps. Countering antibiotic resistance mediated by these efflux pumps is still a major clinical challenge. Among these efflux pumps, NorA of S. aureus actively expels a broad spectrum of antibiotics, significantly decreasing intracellular drug accumulation and thereby compromising therapeutic efficacy. It is a well-known contributor in drug resistance, yet no clinically approved inhibitors are available. This study reports the synthesis of some sulfone functionalized thioproline appended α/γ hybrid peptides and in silico evaluation as a novel class of NorA efflux pump inhibitors. Molecular docking and binding energy analysis identified peptide 4b as the most potent in-silico candidate among the synthesized series of peptides targeting NorA of S. aureus. MD Simulation and Hydrogen bond analysis reveals that these peptides bind to key functional residues in NorA, effectively inhibiting its function without any membrane permeation. This work highlights a new direction for overcoming efflux-mediated resistance. Nevertheless, experimental corroboration remains vital to support its inhibitory potential and therapeutic applicability.