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PMID: 15767566 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 102 ·No. 12 ·2005-03-22 ·Pages 4548-53

Weinstein EA, Yano T, Li LS, Avarbock D, Avarbock A, Helm D, McColm AA, Duncan K, Lonsdale JT, Rubin H

Abstract

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.

MeSH Terms
Animals Antitubercular Agents/chemistry,pharmacology Electron Transport/genetics Electron Transport Complex III/metabolism Enzyme Inhibitors/chemistry,pharmacology Escherichia coli/genetics Female Genes, Bacterial Mice Mice, Inbred BALB C Mycobacterium tuberculosis/drug effects,enzymology,genetics Oxygen Consumption/drug effects Phenothiazines/chemistry,pharmacology Quinone Reductases/antagonists & inhibitors,genetics Recombinant Proteins/antagonists & inhibitors,genetics Tuberculosis, Pulmonary/drug therapy,microbiology
Chemicals
Antitubercular Agents Enzyme Inhibitors Phenothiazines Recombinant Proteins Quinone Reductases Electron Transport Complex III
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Weinstein Edward A
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Yano Takahiro
Li Lin-Sheng
Avarbock David
Avarbock Andrew
Helm Douglas
McColm Andrew A
Duncan Ken
Lonsdale John T
Rubin Harvey
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0500469102
Published
2005-03-22
Epub
2005-00-14
Pages
4548-53
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC555520
Subset
IM
Grants
NIAID NIH HHS · R01 AI043420 · United States
NIAID NIH HHS · AI43420 · United States
External Links
PubMed source DOI: 10.1073/pnas.0500469102 PMC Full Text View journal details
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