Tuberculosis (TB), which is caused by the intracellular pathogen, Mycobacterium tuberculosis (Mtb), remains one of the deadliest infectious diseases worldwide, accounting for 1.45 million deaths?in?2018[1].?Thus,?there?is?an?increasing?need?to develop new antibiotics or to repurpose old drugs that have the potential to shorten the current duration of therapy. Metronidazole (MTZ) is a 5-nitroimidazole antibiotic that is mainly used in the treatment of anaerobic and protozoal infections[2]. The action of mechanism for metronidazole has not been fully established. As a prodrug, MTZ is inactive until taken up and reduced by anaerobic bacteria and?protozoa.?It?is?possible?that?the?reduction?of?Mtz leads to the production of toxic metabolites, which bind?to?deoxyribonucleic?acid?and?electron-transport proteins of microbial pathogens, thus blocking nucleic acid synthesis[3]. The impressive potency of MTZ against anaerobic bacteria indicates the potential for killing Mtb under anaerobic conditions. A?previous?in vitro?study?demonstrated?that?MTZ?has potent activity against tubercle bacilli under anaerobic conditions[4]. In a non-human primate model, MTZ has been shown to prevent reactivation of latent Mtb infection, indicating the in vivo role in targeting Mtb within an anaerobic environment[5]. Although?there?is?strong?evidence?for?the?role?of?MTZ in affecting anaerobic bacilli, the mechanism of action has not been elucidated in Mtb considering that MTZ must be catalyzed to a nitro-free radical form with endogenous nitroreductase. To provide insight?=?into?how?MTZ?is?activated?in?anaerobic?Mtb bacilli, we first characterized the nitroreductase gene, Rv3131, and identified the key residue conferring?the?activation?of?MTZ?in?Mtb.

DONG Wen Zhu;SHI Jin;CHU Ping;LIU Rong Mei;WEN Shu An;ZHANG Ting Ting;PANG Yu;LU Jie

Department of Infectious Diseases,The First People's Hospital of Ziyang,Ziyang 641300,Sichuan,China;Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute,Beijing 101149,China;Department of Tuberculosis,Beijing Chest Hospital,Capital Medical University,Beijing 101149,China;Beijing Key Laboratory for Pediatric Diseases of Otolaryngology,Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital,Capital Medical University, National Center for Children's Health, Beijing 101149, China

生物医学与环境科学（英文版）

[1]DONG Wen Zhu;SHI Jin;CHU Ping;LIU Rong Mei;WEN Shu An;ZHANG Ting Ting;PANG Yu;LU Jie-.The putative NAD(P)H Nitroreductase, Rv3131, is the Probable Activating Enzyme for Metronidazole in Mycobacterium Tuberculosis)[J].生物医学与环境科学（英文版）,2022(07):652-656

Nitroreductase,Rv3131,Metronidazole,repurpose,nitroimidazole,protozoal,Mtz

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