Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps
Coline Plé1, Heng-Keat Tam2,3, Anais Vieira Da Cruz4
1Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000, Lille, France.
Nature Communications
|January 11, 2022
Summary
Researchers discovered new pyridylpiperazine compounds that enhance antibiotic effectiveness by blocking the AcrAB-TolC efflux pump in E. coli. These allosteric inhibitors target a unique site, preventing the pump
Area of Science:
- Microbiology
- Structural Biology
- Medicinal Chemistry
Background:
- Gram-negative bacteria utilize Resistance-Nodulation-Division (RND) family efflux pumps to confer multidrug resistance.
- The AcrAB-TolC efflux pump is a primary target for overcoming antibiotic resistance in Escherichia coli (E. coli).
Purpose of the Study:
- To identify and optimize novel compounds that inhibit the AcrAB-TolC efflux pump.
- To elucidate the mechanism of action and binding site of these novel inhibitors.
Main Methods:
- Chemical optimization of pyridylpiperazine-based compounds.
- Characterization of resistant E. coli mutants.
- Structural biology analyses and molecular dynamics simulations.
Main Results:
- Pyridylpiperazine compounds were identified that potentiate antibiotic activity by inhibiting the AcrAB-TolC pump.
- Structural and simulation data revealed a unique binding site on the AcrB L protomer's transmembrane domain.
- Inhibitors access the binding pocket from the cytoplasm via a specific channel.
Conclusions:
- A novel class of allosteric efflux pump inhibitors has been discovered.
- These inhibitors likely function by disrupting the catalytic cycle of RND pumps.
- This finding offers a new strategy to combat multidrug resistance in Gram-negative bacteria.
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