Abstract
AbstractThe 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.
Funder
Accelerator Grant from the Biological Discovery through Chemical Innovation (BDCI) initiative, Emory University (to G.L.C. and W.M.W.).
U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences
Cystic Fibrosis Foundation
L.G.K. also gratefully acknowledges support from Dr. John and Linda McGowan from the Atlanta Chapter of ARCS Foundation.
ACS MEDI Pre-doctoral Fellowship
Publisher
Springer Science and Business Media LLC
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