Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs.
Mycobacterium tuberculosis (Mtb) is an obligate aerobe that is capable of long-term persistence under conditions of low oxygen tension. Analysis of the Mtb genome predicts the existence of a branched aerobic respiratory chain terminating in a cytochrome bd system and a cytochrome aa(3) system. Both chains can be initiated with type II NADH:menaquinone oxidoreductase. We present a detailed biochemical characterization of the aerobic respiratory chains from Mtb and show that phenothiazine analogs specifically inhibit NADH:menaquinone oxidoreductase activity. The emergence of drug-resistant strains of Mtb has prompted a search for antimycobacterial agents. Several phenothiazines analogs are highly tuberculocidal in vitro, suppress Mtb growth in a mouse model of acute infection, and represent lead compounds that may give rise to a class of selective antibiotics.
Weinstein
Edward A
EA
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Yano
Takahiro
T
Li
Lin-Sheng
LS
Avarbock
David
D
Avarbock
Andrew
A
Helm
Douglas
D
McColm
Andrew A
AA
Duncan
Ken
K
Lonsdale
John T
JT
Rubin
Harvey
H
D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D004579:Electron Transport / Q000235:genetics; D014450:Electron Transport Complex III / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D005798:Genes, Bacterial; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D010101:Oxygen Consumption / Q000187:drug effects; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology; D011808:Quinone Reductases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000382:microbiology
D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D010640:Phenothiazines; D011994:Recombinant Proteins; D011808:Quinone Reductases; D014450:Electron Transport Complex III