Studies on the Adjuvant Potential of Synthetic Ligands for Targeting MRSA in Combination Therapy

Abstract

quotMethicillin-resistant Staphylococcus aureus (MRSA) is a major healthcare concern as the pathogen is not only associated with newlinehospital-acquired infections but also holds implications in community-acquired infections. Mitigation of MRSA infection is an newlinearduous task as the number of therapeutic antibiotics effective against clinical strains of MRSA are limited. This crisis underpins newlinea critical need to develop antagonistic agents that can counter the resistance mechanism and resensitize the pathogen against therapeutic antibiotics. To address this pertinent healthcare issue, the current work highlights the adjuvant potential of rationally designed synthetic efflux pump inhibitor (EPI) and membrane-targeting antibacterials to counter the core resistance mechanism in MRSA and restore susceptibility of the pathogen to low doses of a therapeutic antibiotic. As a first objective, the potential of newlineurea-based synthetic ligands (C1-C8) as an EPI was studied. Amongst the ligands, C8 could significantly inhibit efflux pump newlineactivity, downregulate expression of norA gene, reduce the minimum inhibitory concentration (MIC) of ciprofloxacin (CPX) by newline16-fold and prevent emergence of CPX resistance in a clinical strain of MRSA till 120 generations. The therapeutic potency of C8 was leveraged by generating a C8-loaded PLGA nanocarrier (C8-PNC), which displayed EPI activity and could potentiate the newlineefficacy of CPX against MRSA. Further, the payload nanocarrier (C8-PNC) was non-toxic to HEK-293 cells and could effectively newlinehinder adhesion of MRSA cells onto collagen in combination with CPX. It is acknowledged that the bacterial cell membrane is a newlineformidable permeability barrier for antibiotics. Hence, it was conceived that antibacterials that can breach the membrane hold significant prospect against MRSA. Amongst a set of quinoxaline-based synthetic ligands (C1-C4), the ligand C2 could newlineremarkably impede MRSA cell growth, with an MIC of 32 and#956;M, render dose-dependent membrane-directed activity and inhibit MRSA biofilm formation. A quantita