Involvement of Holliday junction resolvase in fluoroquinolone-mediated killing of Mycobacterium smegmatis

Quanxin Long; Qinglin Du; Tiwei Fu; Karl Drlica; Xilin Zhao; Jianping Xie

doi:10.1128/AAC.04434-14

Involvement of Holliday junction resolvase in fluoroquinolone-mediated killing of Mycobacterium smegmatis

Antimicrob Agents Chemother. 2015 Mar;59(3):1782-5. doi: 10.1128/AAC.04434-14. Epub 2014 Dec 22.

Authors

Quanxin Long¹, Qinglin Du², Tiwei Fu², Karl Drlica³, Xilin Zhao⁴, Jianping Xie⁵

Affiliations

¹ Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Ministry of Education Eco-Environment of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University, Beibei District, Chongqing, China Second Affiliated Hospital and the Key Laboratory of Molecular Biology of Infectious Diseases of the Ministry of Education, Chongqing Medical University, Yuzhong District, Chongqing, China.
² Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Ministry of Education Eco-Environment of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University, Beibei District, Chongqing, China.
³ Public Health Research Institute and Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA.
⁴ Public Health Research Institute and Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiang-An District, Xiamen, Fujian Province, China zhaox5@njms.rutgers.edu georgex@swu.edu.cn.
⁵ Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Ministry of Education Eco-Environment of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University, Beibei District, Chongqing, China zhaox5@njms.rutgers.edu georgex@swu.edu.cn.

Abstract

The absence of the Holliday-junction Ruv resolvase of Mycobacterium smegmatis increased the bacteriostatic and bactericidal activities of the fluoroquinolone moxifloxacin, an important antituberculosis agent. The treatment of ruvAB-deficient cells with thiourea and 2,2'-bipyridyl lowered moxifloxacin lethality to wild-type levels, indicating that the absence of ruvAB stimulates a lethal pathway involving reactive oxygen species. A hexapeptide that traps the Holliday junction substrate of RuvAB potentiated moxifloxacin-mediated lethality, supporting the development of small-molecule enhancers for moxifloxacin activity against mycobacteria.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antitubercular Agents / pharmacology
DNA, Cruciform / drug effects
DNA, Cruciform / metabolism
DNA-Binding Proteins / metabolism
Fluoroquinolones / pharmacology*
Holliday Junction Resolvases / metabolism*
Moxifloxacin
Mycobacterium smegmatis / drug effects*
Mycobacterium smegmatis / metabolism*
Reactive Oxygen Species / metabolism
Thiourea / pharmacology

Substances

Antitubercular Agents
DNA, Cruciform
DNA-Binding Proteins
Fluoroquinolones
Reactive Oxygen Species
Holliday Junction Resolvases
Thiourea
Moxifloxacin

Abstract

Publication types

MeSH terms

Substances

Grants and funding