Document Detail


A common mechanism of inhibition of the Mycobacterium tuberculosis mycolic acid biosynthetic pathway by isoxyl and thiacetazone.
MedLine Citation:
PMID:  23002234     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Isoxyl (ISO) and thiacetazone (TAC), two prodrugs once used in the clinical treatment of tuberculosis, have long been thought to abolish Mycobacterium tuberculosis (M. tuberculosis) growth through the inhibition of mycolic acid biosynthesis, but their respective targets in this pathway have remained elusive. Here we show that treating M. tuberculosis with ISO or TAC results in both cases in the accumulation of 3-hydroxy C(18), C(20), and C(22) fatty acids, suggestive of an inhibition of the dehydratase step of the fatty-acid synthase type II elongation cycle. Consistently, overexpression of the essential hadABC genes encoding the (3R)-hydroxyacyl-acyl carrier protein dehydratases resulted in more than a 16- and 80-fold increase in the resistance of M. tuberculosis to ISO and TAC, respectively. A missense mutation in the hadA gene of spontaneous ISO- and TAC-resistant mutants was sufficient to confer upon M. tuberculosis high level resistance to both drugs. Other mutations found in hypersusceptible or resistant M. tuberculosis and Mycobacterium kansasii isolates mapped to hadC. Mutations affecting the non-essential mycolic acid methyltransferases MmaA4 and MmaA2 were also found in M. tuberculosis spontaneous ISO- and TAC-resistant mutants. That MmaA4, at least, participates in the activation of the two prodrugs as proposed earlier is not supported by our biochemical evidence. Instead and in light of the known interactions of both MmaA4 and MmaA2 with HadAB and HadBC, we propose that mutations affecting these enzymes may impact the binding of ISO and TAC to the dehydratases.
Authors:
Anna E Grzegorzewicz; Jana Korduláková; Victoria Jones; Sarah E M Born; Juan M Belardinelli; Adrien Vaquié; Vijay A K B Gundi; Jan Madacki; Nawel Slama; Françoise Laval; Julien Vaubourgeix; Rebecca M Crew; Brigitte Gicquel; Mamadou Daffé; Hector R Morbidoni; Patrick J Brennan; Annaik Quémard; Michael R McNeil; Mary Jackson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-09-21
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-12     Completed Date:  2013-01-31     Revised Date:  2013-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  38434-41     Citation Subset:  IM    
Affiliation:
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523-1682, USA.
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MeSH Terms
Descriptor/Qualifier:
Alleles
Antitubercular Agents / pharmacology
Cell Wall / metabolism
Chromatography, Liquid / methods
Fatty Acid Synthetase Complex / metabolism
Gas Chromatography-Mass Spectrometry / methods
Genome, Bacterial
Lipids / chemistry
Mass Spectrometry / methods
Models, Chemical
Mycobacterium bovis / metabolism*
Mycobacterium tuberculosis / metabolism*
Mycolic Acids / antagonists & inhibitors*
Phenylthiourea / analogs & derivatives*,  pharmacology
Recombinant Proteins / chemistry
Sequence Analysis, DNA
Thioacetazone / pharmacology*
Time Factors
Grant Support
ID/Acronym/Agency:
AI063054/AI/NIAID NIH HHS; AI085992/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antitubercular Agents; 0/Lipids; 0/Mycolic Acids; 0/Recombinant Proteins; 103-85-5/Phenylthiourea; 104-06-3/Thioacetazone; 43M23X81Y2/thiocarlide; EC 6.-/Fatty Acid Synthetase Complex
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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