TY - JOUR
T1 - Persister control by leveraging dormancy associated reduction of antibiotic efflux
AU - Roy, Sweta
AU - Bahar, Ali Adem
AU - Gu, Huan
AU - Nangia, Shikha
AU - Sauer, Karin
AU - Ren, Dacheng
N1 - Publisher Copyright:
© 2021 Roy et al.
PY - 2021/12
Y1 - 2021/12
N2 - Persistent bacterial infections do not respond to current antibiotic treatment 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.
AB - Persistent bacterial infections do not respond to current antibiotic treatment 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.
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U2 - 10.1371/journal.ppat.1010144
DO - 10.1371/journal.ppat.1010144
M3 - Article
C2 - 34890435
AN - SCOPUS:85121331870
SN - 1553-7366
VL - 17
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 12
M1 - e1010144
ER -