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<p>The rise of antimicrobial resistance (AMR) of the routinely used antibiotics is ineffective against drug–resistant pathogenic strains of <i>Escherichia coli,</i> set off with limited treatment choices, costs, and increasing mortality rates. Multidrug efflux pumps have been identified as crucial determinants of AMR, flushing numerous antibiotics from cells in a non-specific way, and have emerged as promising drug targets to overcome AMR. Herein, the work focuses on determining structural and mutational insights of tripartite efflux pump subunit AcrB by executing multiple sequence alignment (MSA); the residues 615 and 617 at the substrate-binding site were identified mutated from an aromatic amino acid, phenylalanine, to an aliphatic amino acid, alanine. The study proceeded with the co-development of AcrB antagonist’s by applying pharmacokinetic parameters filters to 40,613 natural compounds and molecular docking of single compounds, multiple ligand simultaneous docking (MLSD), molecular dynamics (MD) simulations, principal component analysis (PCA), and free energy landscape (FEL) analysis by considering resistant antibiotics. The identified mutations in the AcrB subunit are responsible for upregulating the activity of the AcrAB-TolC efflux pump and leading to a reduced concentration of antibiotics in the bacterial cytoplasm, ultimately increasing antibiotic resistance. Furthermore, based upon compound screening against target AcrB, 3-Hydroxyfumiquinazoline A shows competitive interaction with the antibiotic Erythromycin. A similar interaction pattern was observed between Sungucine and Cheatoglobosin D with Novobiocin while Procheatoglobosin I and Chaetoglobosin Q with Fusidic acid. Our findings highlight a novel class of efflux pump inhibitors (EPIs) that effectively antagonize the AcrB subunit and could serve as novel adjuvant alternatives for reviving antibiotic activity in resistant bacteria.</p> Graphical abstract <p></p>

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Co-development of efflux pump inhibitors with antibiotics on targeting structural and mutational aspects of AcrB subunit

  • 期刊论文

  • 发表日期：

    2025年4月27日

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  • Shweta Singh Chauhan,
  • Tanya Jamal,
  • Anshika Gupta,
  • Ramakrishnan Parthasarathi

摘要

The rise of antimicrobial resistance (AMR) of the routinely used antibiotics is ineffective against drug–resistant pathogenic strains of Escherichia coli, set off with limited treatment choices, costs, and increasing mortality rates. Multidrug efflux pumps have been identified as crucial determinants of AMR, flushing numerous antibiotics from cells in a non-specific way, and have emerged as promising drug targets to overcome AMR. Herein, the work focuses on determining structural and mutational insights of tripartite efflux pump subunit AcrB by executing multiple sequence alignment (MSA); the residues 615 and 617 at the substrate-binding site were identified mutated from an aromatic amino acid, phenylalanine, to an aliphatic amino acid, alanine. The study proceeded with the co-development of AcrB antagonist’s by applying pharmacokinetic parameters filters to 40,613 natural compounds and molecular docking of single compounds, multiple ligand simultaneous docking (MLSD), molecular dynamics (MD) simulations, principal component analysis (PCA), and free energy landscape (FEL) analysis by considering resistant antibiotics. The identified mutations in the AcrB subunit are responsible for upregulating the activity of the AcrAB-TolC efflux pump and leading to a reduced concentration of antibiotics in the bacterial cytoplasm, ultimately increasing antibiotic resistance. Furthermore, based upon compound screening against target AcrB, 3-Hydroxyfumiquinazoline A shows competitive interaction with the antibiotic Erythromycin. A similar interaction pattern was observed between Sungucine and Cheatoglobosin D with Novobiocin while Procheatoglobosin I and Chaetoglobosin Q with Fusidic acid. Our findings highlight a novel class of efflux pump inhibitors (EPIs) that effectively antagonize the AcrB subunit and could serve as novel adjuvant alternatives for reviving antibiotic activity in resistant bacteria.

Graphical abstract