Disruption of Membrane by Colistin Kills Uropathogenic Escherichia coli Persisters and Enhances Killing of Other Antibiotics.
Persisters are small populations of quiescent bacterial cells that survive exposure to bactericidal antibiotics and are responsible for many persistent infections and posttreatment relapses. However, little is known about how to effectively kill persister bacteria. In the work presented here, we found that colistin, a membrane-active antibiotic, was highly active against Escherichia coli persisters at high concentrations (25 or 50 μg/ml). At a clinically relevant lower concentration (10 μg/ml), colistin alone had no apparent effect on E. coli persisters. In combination with other drugs, this concentration of colistin enhanced the antipersister activity of gentamicin and ofloxacin but not that of ampicillin, nitrofurans, and sulfa drugs in vitro The colistin enhancement effect was most likely due to increased uptake of the other antibiotics, as demonstrated by increased accumulation of fluorescence-labeled gentamicin. Interestingly, colistin significantly enhanced the activity of ofloxacin and nitrofurantoin but not that of gentamicin or sulfa drugs in the murine model of urinary tract infection. Our findings suggest that targeting bacterial membranes is a valuable approach to eradicating persisters and should have implications for more effective treatment of persistent bacterial infections.
Key Laboratory of Molecular Virology, Institute of Medical Microbiology, Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.|Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
Peng
P
Cui
Lanzhou Center for Tuberculosis Research and Institute of Pathogenic Biology and Gansu Provincial Key Laboratory of Evidence Based Medicine and Clinical Translation, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
Hongxia
H
Niu
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
Wanliang
W
Shi
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
Shuo
S
Zhang
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
Hao
H
Zhang
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
Joseph
J
Margolick
Key Laboratory of Molecular Virology, Institute of Medical Microbiology, Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China zhangwenhong@fudan.edu.cn yzhang@jhsph.edu.
Wenhong
W
Zhang
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA zhangwenhong@fudan.edu.cn yzhang@jhsph.edu.|Key Laboratory of Molecular Virology, Institute of Medical Microbiology, Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
Ying
Y
Zhang
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D003091:Colistin / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004927:Escherichia coli Infections / Q000188:drug therapy; D048168:Escherichia coli K12 / Q000187:drug effects; D005260:Female; D005839:Gentamicins / Q000493:pharmacokinetics / Q000494:pharmacology; D008809:Mice, Inbred C3H; D008826:Microbial Sensitivity Tests; D014552:Urinary Tract Infections / Q000188:drug therapy / Q000382:microbiology; D056689:Uropathogenic Escherichia coli / Q000166:cytology / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D005839:Gentamicins; D003091:Colistin