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, and Cryptococcus 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 modeling. 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.
Part of the book: Biomarkers and Bioanalysis Overview
Mammalian ABCB1 P-glycoprotein is an ATP- dependent efflux pump with broad substrate specificity associated with cellular drug resistance. Homologous to this role in mammalian biology, the P-glycoprotein of agents of neglected tropical diseases (NTDs) mediates the emergence of multidrug-resistance phenotypes. The clinical and socioeconomic implications of NTDs are exacerbated by the lack of research interest among Big Pharma for treating such conditions. This work aims to characterise P-gp homologues in certain agents of key NTDs, namely (1) Protozoa: Leishmania major, Trypanosoma cruzi; (2) Helminths: Onchocerca volvulus, Schistosoma mansoni. Based on structural modelling of the organismal P-gp homologues, potential antibiotics targeting these structures were identified based on similarity and repurposing of existing drugs. Docking studies of the Pgp receptor—antibiotic ligand complexes were carried out and the most tenable target-ligand conformations assessed. The interacting residues were identified, and binding pockets studied. The in silico studies yielded measurements of the relative efficacy of the new drugs, which need experimental validation. Our studies could lay the foundation for the development of effective synergistic or new therapies against key neglected tropical diseases. The potential mechanisms of multidrug resistance emergence in E. coli were examined.
Part of the book: E. Coli Infections