PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release.
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.
Singh
Ramandeep
R
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
Manjunatha
Ujjini
U
Boshoff
Helena I M
HI
Ha
Young Hwan
YH
Niyomrattanakit
Pornwaratt
P
Ledwidge
Richard
R
Dowd
Cynthia S
CS
Lee
Ill Young
IY
Kim
Pilho
P
Zhang
Liang
L
Kang
Sunhee
S
Keller
Thomas H
TH
Jiricek
Jan
J
Barry
Clifton E
CE
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
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