Document Detail


Mutation of tlyA confers capreomycin resistance in Mycobacterium tuberculosis.
MedLine Citation:
PMID:  15673735     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Capreomycin, an important drug for the treatment of multidrug-resistant tuberculosis, is a macrocyclic peptide antibiotic produced by Saccharothrix mutabolis subspecies capreolus. The basis of resistance to this drug was investigated by isolating and characterizing capreomycin-resistant strains of Mycobacterium smegmatis and Mycobacterium tuberculosis. Colonies resistant to capreomycin were recovered from a library of transposon-mutagenized M. smegmatis. The transposon insertion site of one mutant was mapped to an open reading frame in the unfinished M. smegmatis genome corresponding to the tlyA gene (Rv1694) in the M. tuberculosis H37Rv genome. In M. smegmatis spontaneous capreomycin-resistant mutants, the tlyA gene was disrupted by one of three different naturally occurring insertion elements. Genomic DNAs from pools of transposon mutants of M. tuberculosis H37Rv were screened by PCR by using primers to the tlyA gene and the transposon to detect mutants with an insertion in the tlyA gene. One capreomycin-resistant mutant was recovered that contained the transposon inserted at base 644 of the tlyA gene. Complementation with the wild-type tlyA gene restored susceptibility to capreomycin in the M. smegmatis and M. tuberculosis tlyA transposon mutants. Mutations were found in the tlyA genes of 28 spontaneous capreomycin-resistant mutants generated from three different M. tuberculosis strains and in the tlyA genes of capreomycin-resistant clinical isolates. In in vitro transcription-translation assays, ribosomes from tlyA mutant but not tlyA(+) strains resist capreomycin inhibition of transcription-translation. Therefore, TlyA appears to affect the ribosome, and mutation of tlyA confers capreomycin resistance.
Authors:
Courtney E Maus; Bonnie B Plikaytis; Thomas M Shinnick
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  49     ISSN:  0066-4804     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2005 Feb 
Date Detail:
Created Date:  2005-01-27     Completed Date:  2005-03-29     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  571-7     Citation Subset:  IM    
Affiliation:
Program in Microbiology and Molecular Genetics, Emory University, Atlanta, Georgia, USA.
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MeSH Terms
Descriptor/Qualifier:
Antibiotics, Antitubercular / pharmacology*
Bacterial Proteins / genetics*
Blotting, Southern
Capreomycin / pharmacology*
Cloning, Molecular
DNA Transposable Elements / genetics
DNA, Bacterial / biosynthesis,  genetics
Drug Resistance, Bacterial
Gene Library
Hemolysin Proteins / genetics*
Humans
Microbial Sensitivity Tests
Mutagenesis
Mutation / genetics*
Mycobacterium smegmatis / drug effects,  genetics
Mycobacterium tuberculosis / drug effects*,  genetics*
Plasmids
Protein Biosynthesis
RNA, Bacterial / genetics
RNA, Ribosomal, 16S / genetics
Reverse Transcriptase Polymerase Chain Reaction
Transcription, Genetic
Tuberculosis / microbiology
Viomycin / pharmacology
Chemical
Reg. No./Substance:
0/Antibiotics, Antitubercular; 0/Bacterial Proteins; 0/DNA Transposable Elements; 0/DNA, Bacterial; 0/Hemolysin Proteins; 0/RNA, Bacterial; 0/RNA, Ribosomal, 16S; 0/TlyA protein, Mycobacterium tuberculosis; 11003-38-6/Capreomycin; 32988-50-4/Viomycin
Comments/Corrections

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


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