Structure-Based Design of Promysalin Analogues to Overcome Mechanisms of Bacterial Resistance

• Type of Material: Article
• Authors: Andrew R Mahoney, Emory University; Kelly M Storek, Genentech, Inc., South San Francisco; William Wuest, Emory University
• Language: English
• Date: 2023-03-22
• Publisher: AMER CHEMICAL SOC
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors. Published by American Chemical Society
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1021/acsomega.3c00884
• Title of Journal or Parent Work: ACS OMEGA
• Volume: 8
• Issue: 13
• Start Page: 12558
• End Page: 12564
• Keywords: Chemistry; Chemistry, Multidisciplinary; Science & Technology; DRUGS; INFECTIONS; Physical Sciences
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

The search for antibiotics that function through novel mechanisms of action is ongoing, and recent progress in our lab identified the tricarboxylic acid cycle as a viable option. Promysalin is a secondary metabolite capable of species-specific inhibition of Pseudomonas aeruginosa, a common opportunistic pathogen. Promysalin disrupts primary metabolism in this bacterium by competitively inhibiting succinate dehydrogenase at the ubiquinone binding site. However, the activity of promysalin in cellulo is marred potentially by its chemical instability and/or propensity for efflux. To assess the success of these novel analogues, a novel strain of P. aeruginosa harboring gene deletions of eight efflux pumps and porins was developed and implemented. Herein, we disclose the synthesis and biological investigation of six promysalin analogues to overcome these liabilities and demonstrate that efflux likely plays a significant role in tolerating the effect of the inhibitor.