DOI: 10.1002/jcc.27215 ISSN:

Discovering targeted inhibitors for Escherichia coli efflux pump fusion proteins using computational and structure‐guided approaches

Shweta Singh Chauhan, Anshika Gupta, Aashna Srivastava, Ramakrishnan Parthasarathi
  • Computational Mathematics
  • General Chemistry


Multidrug resistance pathogens causing infections and illness remain largely untreated clinically. Efflux pumps are one of the primary processes through which bacteria develop resistance by transferring antibiotics from the interior of their cells to the outside environment. Inhibiting these pumps by developing efficient derivatives appears to be a promising strategy for restoring antibiotic potency. This investigation explores literature‐reported inhibitors of E. coli efflux pump fusion proteins AcrB‐AcrA and identify potential chemical derivatives of these inhibitors to overcome the limitations. Using computational and structure‐guided approaches, a study was conducted with the selected inhibitors (AcrA:25‐AcrB:59) obtained by data mining and their derivatives (AcrA:857‐AcrB:3891) to identify their inhibitory effect on efflux pump using virtual screening, molecular docking and density functional theory (DFT) calculations. The finding indicates that Compound 2 (ZINC000072136376) has shown better binding and a significant inhibitory effect on AcrA, while Compound 3 (ZINC000072266819) has shown stronger binding and substantial inhibition effect on both non‐mutant and mutated AcrB subunits. The identified derivatives could exhibit a better inhibitor and provide a potential approach for restoring the actions of resistant antibiotics.

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