Document Detail


ACCase 6 is the essential acetyl-CoA carboxylase involved in fatty acid and mycolic acid biosynthesis in mycobacteria.
MedLine Citation:
PMID:  19423629     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mycolic acids are essential for the survival, virulence and antibiotic resistance of the human pathogen Mycobacterium tuberculosis. Inhibitors of mycolic acid biosynthesis, such as isoniazid and ethionamide, have been used as efficient drugs for the treatment of tuberculosis. However, the increase in cases of multidrug-resistant tuberculosis has prompted a search for new targets and agents that could also affect synthesis of mycolic acids. In mycobacteria, the acyl-CoA carboxylases (ACCases) provide the building blocks for de novo fatty acid biosynthesis by fatty acid synthase (FAS) I and for the elongation of FAS I products by the FAS II complex to produce meromycolic acids. By generating a conditional mutant in the accD6 gene of Mycobacterium smegmatis, we demonstrated that AccD6 is the essential carboxyltransferase component of the ACCase 6 enzyme complex implicated in the biosynthesis of malonyl-CoA, the substrate of the two FAS enzymes of Mycobacterium species. Based on the conserved structure of the AccD5 and AccD6 active sites we screened several inhibitors of AccD5 as potential inhibitors of AccD6 and found that the ligand NCI-172033 was capable of inhibiting AccD6 with an IC(50) of 8 microM. The compound showed bactericidal activity against several pathogenic Mycobacterium species by producing a strong inhibition of both fatty acid and mycolic acid biosynthesis at minimal inhibitory concentrations. Overexpression of accD6 in M. smegmatis conferred resistance to NCI-172033, confirming AccD6 as the main target of the inhibitor. These results define the biological role of a key ACCase in the biosynthesis of membrane and cell envelope fatty acids, and provide a new target, AccD6, for rational development of novel anti-mycobacterial drugs.
Authors:
Daniel G Kurth; Gabriela M Gago; Agustina de la Iglesia; Bernardo Bazet Lyonnet; Ting-Wan Lin; Héctor R Morbidoni; Shiou-Chuan Tsai; Hugo Gramajo
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-05-07
Journal Detail:
Title:  Microbiology (Reading, England)     Volume:  155     ISSN:  1350-0872     ISO Abbreviation:  Microbiology (Reading, Engl.)     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-07-29     Completed Date:  2009-10-08     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  9430468     Medline TA:  Microbiology     Country:  England    
Other Details:
Languages:  eng     Pagination:  2664-75     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Anti-Infective Agents / administration & dosage
Biosynthetic Pathways / drug effects
Carbon-Carbon Ligases / antagonists & inhibitors,  genetics,  metabolism*
Chlorobenzenes / administration & dosage
Dose-Response Relationship, Drug
Drug Resistance, Bacterial
Humans
Microbial Sensitivity Tests
Mycobacterium smegmatis / drug effects,  enzymology*,  genetics
Mycobacterium tuberculosis / drug effects,  enzymology
Mycolic Acids / metabolism*
Phenols / administration & dosage
Tuberculosis, Pulmonary / microbiology*
Grant Support
ID/Acronym/Agency:
1R03TW007982-02/TW/FIC NIH HHS; R01 AI076460/AI/NIAID NIH HHS; R01 GM100305/GM/NIGMS NIH HHS; R03 AI073426/AI/NIAID NIH HHS; R03 AI073426-01A1/AI/NIAID NIH HHS; R03 AI073426-02/AI/NIAID NIH HHS; R03 TW007982/TW/FIC NIH HHS; R03 TW007982-02/TW/FIC NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Infective Agents; 0/Chlorobenzenes; 0/Mycolic Acids; 0/NCI-172033; 0/Phenols; EC 6.4.-/Carbon-Carbon Ligases; EC 6.4.1.-/acyl-CoA carboxylase
Comments/Corrections

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


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