Identification of potential therapeutics by targeting AcrB protein from AcrAB-TolC multidrug efflux pump of Escherichia coli: an in-silico exploration

Antibiotic resistance, a critical global health concern, arises as bacteria and other microbes evolve to resist drugs. The AcrB protein, a key component of the AcrAB-TolC multidrug efflux pump in Escherichia coli, plays a significant role in antibiotic resistance and presents an opportunity for new drug development. Inhibiting this pump has the potential to reverse antibiotic resistance and restore drug efficacy. This study explores potential molecules that target the AcrB protein as a novel therapeutic strategy against multidrug-resistant (MDR) Gram-negative bacteria, utilizing in-silico techniques. The initial step in the selection of ligands involved gathering compounds from the PubChem database that are structurally similar to erythromycin A, with a cutoff score of 80 or higher in the similarity search. Stringent drug-likeness criteria were applied, yielding 111 compounds that share structural similarities with erythromycin A. Virtual screening against the target protein identified 72 compounds with promising docking scores between -6.13 and -3.06 kcal/mol using the MtiOpenScreen web server. Subsequently, four compounds (CID:102055530, CID:101369593, CID:139312504, and CID:143044924), along with the control compound (erythromycin A), were selected for further analysis. These analyses included re-docking, molecular dynamics simulations, free binding energy calculations, and PCA-based free energy landscape investigation. The findings suggest that the identified compounds could serve as foundations for developing new inhibitors targeting the AcrB protein, offering a promising strategy to counteract bacterial resistance. This research supports the need for further experimental validation to confirm these in-silico predictions and to potentially advance these compounds through the drug development process.