Characterization of pyridylpiperazine-based efflux pump inhibitors for Acinetobacter baumannii .
Autor: | Jiménez-Castellanos JC; Université de Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019, UMR 9017, CIIL, Center for Infection and Immunity of Lille, F-59000 Lille, France., Pradel E; Université de Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019, UMR 9017, CIIL, Center for Infection and Immunity of Lille, F-59000 Lille, France., Compagne N; Université de Lille, INSERM, Institut Pasteur de Lille, U1177, Drugs and Molecules for Living Systems, F-59000 Lille, France., Vieira Da Cruz A; Université de Lille, INSERM, Institut Pasteur de Lille, U1177, Drugs and Molecules for Living Systems, F-59000 Lille, France., Flipo M; Université de Lille, INSERM, Institut Pasteur de Lille, U1177, Drugs and Molecules for Living Systems, F-59000 Lille, France., Hartkoorn RC; Université de Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019, UMR 9017, CIIL, Center for Infection and Immunity of Lille, F-59000 Lille, France. |
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Jazyk: | angličtina |
Zdroj: | JAC-antimicrobial resistance [JAC Antimicrob Resist] 2023 Oct 24; Vol. 5 (5), pp. dlad112. Date of Electronic Publication: 2023 Oct 24 (Print Publication: 2023). |
DOI: | 10.1093/jacamr/dlad112 |
Abstrakt: | Objectives: In Acinetobacter baumannii , multidrug efflux pumps belonging to the resistance-nodulation-division (RND) superfamily result in decreased antibiotic susceptibility. Improving the activity of current antibiotics via efflux pump inhibitors (EPIs) represents an attractive alternative approach to control this bacterium. Pyridylpiperazines (PyrPips) are a new class of EPIs that can effectively inhibit the Escherichia coli RND efflux pump AcrAB-TolC and boost the activity of several antibiotics. Here we have evaluated and characterized whether the PyrPip chemical family is also able to boost antibiotic activity through inhibition of the RND efflux pumps in A. baumannii . Methods: Comparative structural modelling and docking, structure-activity relationship studies alongside molecular genetic approaches were deployed to improve, characterize and validate PyrPips' target. Results: We showed that two enhanced PyrPip EPIs are capable of rescuing the activity of different classes of antibiotics in A. baumannii . By expressing A. baumannii main efflux pumps (AdeB, AdeG and AdeJ) individually in E. coli recombinant strains, we could gain further insights about the EPIs' capacity to act upon each pump. Finally, we showed that PyrPip EPIs are mostly acting through AdeJ inhibition via interactions with two key charged residues, namely E959 and E963. Conclusions: Our work demonstrates that PyrPip EPIs are capable of inhibiting RND efflux pumps of A. baumannii, and thus may present a promising chemical scaffold for further development. (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.) |
Databáze: | MEDLINE |
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