Computational Studies of Drug Repurposing Targeting P-Glycoprotein-Mediated Multidrug Resistance Phenotypes in Priority Infectious Agents

Abstract

ABCB1 P-glycoprotein (P-gp) is an ATP-dependent efflux pump with broad substrate specificity associated with cellular drug resistance. Homologous to role in mammalian biology, P-glycoproteins of bacterial and fungal pathogens mediate the emergence of multidrug resistance phenotypes, with widespread clinical/ socioeconomic implications. This work aims to characterize P-gp homologues in certain WHO-prioritized infectious agents, namely (1) bacteria: Acinetobacter baumannii and Staphylococcus aureus and (2) fungi: Aspergillus fumigatus, Candida albicans,andCryptococcus neoformans. PSI-BLAST searches against the genome of each of these organisms confirmed the presence of P-gp homologues. Each homologue was aligned against five known P-gp structures, for structural model-ing. FDA-approved antibiotics used in the current line of therapy were retrieved from PubChem, and potential antibiotics were identified based on similarity and repurposing of the existing drugs. The most tenable target-ligand conformations from docking studies of the respective modeled P-gp structures and the antibiotic ligands were assessed for interacting residues within 4.5 Å of the ligand, probable binding pockets and relative efficacies of the new drugs. Our studies could lay the foundation for the development of effective synergistic or new therapies against these pathogens.