Persister control by leveraging dormancy associated reduction of antibiotic efflux

• Published in: PLoS pathogens 2021-12, Vol.17 (12), p.e1010144-e1010144
• Main Authors: Roy, Sweta, Bahar, Ali Adem, Gu, Huan, Nangia, Shikha, Sauer, Karin, Ren, Dacheng
• Format: Article
• Language: English
• Subjects: Active transport; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antibiotic tolerance; Antibiotics; Bacteria; Bacterial diseases; Bacterial infections; Biology and Life Sciences; Cell division; Cell interaction; Development and progression; Dormancy; Drug dosages; Drug resistance in microorganisms; Drug Resistance, Microbial - drug effects; Drug therapy; E coli; Efflux; Escherichia coli - drug effects; Escherichia coli - metabolism; Escherichia coli Infections; Hypotheses; Infections; Medicine and Health Sciences; Microbiological research; Minocycline; Minocycline - metabolism; Minocycline - pharmacology; Reduction; Research and Analysis Methods; Subpopulations; Tuberculosis
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1010144

Persistent bacterial infections do not respond to current antibiotic treatments and thus present a great medical challenge. These conditions have been linked to the formation of dormant subpopulations of bacteria, known as persister cells, that are growth-arrested and highly tolerant to conventional antibiotics. Here, we report a new strategy of persister control and demonstrate that minocycline, an amphiphilic antibiotic that does not require active transport to penetrate bacterial membranes, is effective in killing Escherichia coli persister cells [by 70.8 ± 5.9% (0.53 log) at 100 μg/mL], while being ineffective in killing normal cells. Further mechanistic studies revealed that persister cells have reduced drug efflux and accumulate more minocycline than normal cells, leading to effective killing of this dormant subpopulation upon wake-up. Consistently, eravacycline, which also targets the ribosome but has a stronger binding affinity than minocycline, kills persister cells by 3 logs when treated at 100 μg/mL. In summary, the findings of this study reveal that while dormancy is a well-known cause of antibiotic tolerance, it also provides an Achilles' heel for controlling persister cells by leveraging dormancy associated reduction of drug efflux.