In-silico interaction studies on the efflux pumps suggest polymyxins to be better substrate for RND efflux pumps in multi-drug resistant strains of Acinetobacter baumannii

Bacterial efflux pumps have emerged as antibiotic resistance determinants and confers multidrug resistance to a broad range of antimicrobials as well as non-antibiotic substances by potentially extruding them out. These are also associated with the virulence and biofilm formation. Thus, development of inhibitors against these effective antibacterial targets can be a highly beneficial approach in order to reverse the multidrug resistance (MDR) in the clinical relevant strains. A keen study on the efflux of foregoing or commonly used antibiotics will contribute in finding substrates that could bind efficiently with these efflux pumps. In the present study, we have explored efflux pumps belonging to Resistance-Nodulation-Division (RND) family as they are found prevalent in gram negative pathogens such as A. baumannii. The two RND efflux pumps under consideration are AdeABC and AcrAB-TolC. For comparative analysis, a non-RND family efflux pump i.e. NorM is selected here. We employed a series of computational techniques ranging from molecular docking to binding free energy estimation and molecular dynamics simulations to determine the binding affinity for different classess of drugs namely aminoglycosides, polymyxins, β-lactams, tetracyclines, glycylcyclines, quinolones and metronidazole against the efflux pumps under study. Our results revealed that class polymyxins has the highest binding affinity with the RND efflux pumps i.e. AcrAB-TolC and AdeABC as well as non-RND efflux pump (NorM). The experimental data was found to much extent in accordance with the binding free energy scores obtained from our in silico analysis. To recapitulate the outcome, polymyxins can possibly be the most efficient substrate for both RND and non-RND efflux pumps, thus, can be used as a reference drug for designing potent efflux pump inhibitors against multi-drug resistant strains.