title: PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release.
abstract: Bicyclic nitroimidazoles, including PA-824, are exciting candidates for the treatment of tuberculosis. These prodrugs require intracellular activation for their biological function. We found that Rv3547 is a deazaflavin-dependent nitroreductase (Ddn) that converts PA-824 into three primary metabolites; the major one is the corresponding des-nitroimidazole (des-nitro). When derivatives of PA-824 were used, the amount of des-nitro metabolite formed was highly correlated with anaerobic killing of Mycobacterium tuberculosis (Mtb). Des-nitro metabolite formation generated reactive nitrogen species, including nitric oxide (NO), which are the major effectors of the anaerobic activity of these compounds. Furthermore, NO scavengers protected the bacilli from the lethal effects of the drug. Thus, these compounds may act as intracellular NO donors and could augment a killing mechanism intrinsic to the innate immune system.
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Singh
authors.forename: Ujjini
authors.initials: U
authors.lastname: Manjunatha
authors.forename: Helena I M
authors.initials: HI
authors.lastname: Boshoff
authors.forename: Young Hwan
authors.initials: YH
authors.lastname: Ha
authors.forename: Pornwaratt
authors.initials: P
authors.lastname: Niyomrattanakit
authors.forename: Richard
authors.initials: R
authors.lastname: Ledwidge
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Dowd
authors.forename: Ill Young
authors.initials: IY
authors.lastname: Lee
authors.forename: Pilho
authors.initials: P
authors.lastname: Kim
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Sunhee
authors.initials: S
authors.lastname: Kang
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
authors.forename: Jan
authors.initials: J
authors.lastname: Jiricek
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
mesh_terms: D000693:Anaerobiosis; D000995:Antitubercular Agents / Q000378:metabolism / Q000494:pharmacology*; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D007113:Immunity, Innate; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009593:Nitroimidazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D009601:Nitroreductases / Q000378:metabolism; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D012256:Riboflavin / Q000031:analogs & derivatives / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000995:Antitubercular Agents; D020030:Nitric Oxide Donors; D009593:Nitroimidazoles; D011355:Prodrugs; D026361:Reactive Nitrogen Species; C410767:pretomanid; D009569:Nitric Oxide; C015084:coenzyme F420; D005954:Glucosephosphate Dehydrogenase; D009601:Nitroreductases; D012256:Riboflavin