Targeting the Bet-Hedging Strategy with an Inhibitor of Bacterial Efflux Capacity Enhances Antibiotic Efficiency and Ameliorates Bacterial Persistence In Vitro

• Published in: Microorganisms (Basel) Vol. 10; no. 10; p. 1966
• Main Authors: Morales, Demosthenes, Micheva-Viteva, Sofiya, Adikari, Samantha, Werner, James, Wolinsky, Murray, Hong-Geller, Elizabeth, Kim, Jinwoo, Ojima, Iwao
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.10.2022; MDPI
• Subjects: ABC transporter; ABC transporters; antibiotic therapy enhancement; Antibiotic tolerance; Antibiotics; apoptosis; Bacteria; Bacterial infections; bacterial persistence; BASIC BIOLOGICAL SCIENCES; Burkholderia; Catabolism; Cell activation; Cell death; Cell division; Dosage and administration; Drug resistance; Drug resistance in microorganisms; E coli; Efflux; efflux inhibitor; efflux inhibitors; Fatty acids; Fluorescence in situ hybridization; Gene expression; Histone deacetylase; histone deacetylase inhibition; histone deacetylase inhibitors; Inhibitors; Lipids; Mammals; Metabolites; Microbiological research; Natural products; Physiological aspects; Polyketide synthase; Populations; Proteins; Tuberculosis; United States; United States > US
• ISSN: 2076-2607; 2076-2607
• DOI: 10.3390/microorganisms10101966

Persistence is a bet-hedging strategy in bacterial populations that increases antibiotic tolerance and leads to the establishment of latent infections. In this study, we demonstrated that a synthetic non-toxic taxane-based reversal agent (tRA), developed as an inhibitor of ABC transporter systems in mammalian cancer cells, enhanced antibiotic killing of persister populations from different pathogens, including Burkholderia, Pseudomonas, Francisella, and Yersinia. Acting as an inhibitor of bacterial efflux at 100 nM, tRA99020 enhanced antibiotic efficiency and suppressed the production of natural products of Burkholderia species polyketide synthase (PKS) function. We demonstrate that the metabolites produced by PKS in response to stress by different antibiotics act as inhibitors of mammalian histone deacetylase activity and stimulate cell death. Applying a single-molecule fluorescence in situ hybridization (smFISH) assay, we analyzed on a single-cell level the activation profiles of the persistence regulating pks gene in Burkholderia thailandensis treated with tRA99020 and antibiotics. We posit that a multi-pronged approach encompassing antibiotic therapies and inhibition of efflux systems and fatty acid catabolism will be required for efficient eradication of persistent bacterial populations.