Abstract
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.
Highlights
Bacterial persister cells are dormant phenotypic variants that are highly tolerant to most antibiotics; and present a major challenge to infection control
We hypothesize that persister cells have reduced drug efflux compared to normal cells and accumulate more antimicrobial agents that can penetrate the membranes of persister cells
We developed a new set of criteria for selecting persister control agents and demonstrated effective control of Escherichia coli persister cells by minocycline, rifamycin SV, and eravacycline
Summary
Despite the past decades of success in infection control by antibiotics, persistent bacterial infections remain challenging such as tuberculosis [1], Lyme disease [2], and chronical infections associated with cystic fibrosis [3] and implanted medical devices [4]. These seemingly different disease conditions face the same challenge, bacterial dormancy, which leads to extremely high levels of antibiotic tolerance. A strategy to eradicate persister cells is urgently needed
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