Di-berberine conjugates as chemical probes of Pseudomonas aeruginosa MexXY-OprM efflux function and inhibition.
| Autor: | Kavanaugh LG; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA., Mahoney AR; Department of Chemistry, Emory University, Atlanta, GA., Dey D; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA., Wuest WM; Department of Chemistry, Emory University, Atlanta, GA.; Emory Antibiotic Resistance Center, Emory University, Atlanta, GA., Conn GL; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA.; Emory Antibiotic Resistance Center, Emory University, Atlanta, GA. |
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| Jazyk: | angličtina |
| Zdroj: | BioRxiv : the preprint server for biology [bioRxiv] 2023 Sep 19. Date of Electronic Publication: 2023 Sep 19. |
| DOI: | 10.1101/2023.03.24.533986 |
| Abstrakt: | The Resistance-Nodulation-Division (RND) efflux pump superfamily is pervasive among Gram-negative pathogens and contributes extensively to clinical antibiotic resistance. The opportunistic pathogen Pseudomonas aeruginosa contains 12 RND-type efflux systems, with four contributing to resistance including MexXY-OprM which is uniquely able to export aminoglycosides. At the site of initial substrate recognition, small molecule probes of the inner membrane transporter (e.g., MexY) have potential as important functional tools to understand substrate selectivity and a foundation for developing adjuvant efflux pump inhibitors (EPIs). Here, we optimized the scaffold of berberine, a known but weak MexY EPI, using an in-silico high-throughput screen to identify di-berberine conjugates with enhanced synergistic action with aminoglycosides. Further, docking and molecular dynamics simulations of di-berberine conjugates reveal unique contact residues and thus sensitivities of MexY from distinct P. aeruginosa strains. This work thereby reveals di-berberine conjugates to be useful probes of MexY transporter function and potential leads for EPI development. Competing Interests: Competing Interests The authors declare no competing interests. |
| Databáze: | MEDLINE |
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