Molecular Genetics of para -Aminosalicylic ...
Document type :
Article dans une revue scientifique: Article original
DOI :
Title :
Molecular Genetics of para -Aminosalicylic Acid Resistance in Clinical Isolates and Spontaneous Mutants of Mycobacterium tuberculosis
Author(s) :
Mathys, Vanessa [Auteur]
Molecular Pathology of Tuberculosis [Brussels]
Wintjens, René [Auteur]
Université libre de Bruxelles [ULB]
Lefevre, Philippe [Auteur]
Institut national de recherches archéologiques préventives [Inrap]
Bertout, Julie [Auteur]
Institut de biologie de Lille - IBL [IBLI]
Singhal, Amit [Auteur]
Singapore Immunology Network [SIgN]
Kiass, Mehdi [Auteur]
Institut Scientifique de Santé Publique [Belgique] - Scientific Institute of Public Health [Belgium] [WIV-ISP]
Kurepina, Natalia [Auteur]
Public Health Research Institute [Newark] [PHRI]
Wang, Xiao-Ming [Auteur]
Mathema, Barun [Auteur]
Baulard, Alain [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Kreiswirth, Barry [Auteur]
Public Health Research Institute [Newark] [PHRI]
Bifani, Pablo [Auteur]
Mycobacterial Immunology [Brussels]
Molecular Pathology of Tuberculosis [Brussels]
Wintjens, René [Auteur]
Université libre de Bruxelles [ULB]
Lefevre, Philippe [Auteur]
Institut national de recherches archéologiques préventives [Inrap]
Bertout, Julie [Auteur]
Institut de biologie de Lille - IBL [IBLI]
Singhal, Amit [Auteur]
Singapore Immunology Network [SIgN]
Kiass, Mehdi [Auteur]
Institut Scientifique de Santé Publique [Belgique] - Scientific Institute of Public Health [Belgium] [WIV-ISP]
Kurepina, Natalia [Auteur]
Public Health Research Institute [Newark] [PHRI]
Wang, Xiao-Ming [Auteur]
Mathema, Barun [Auteur]
Baulard, Alain [Auteur]

Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Kreiswirth, Barry [Auteur]
Public Health Research Institute [Newark] [PHRI]
Bifani, Pablo [Auteur]
Mycobacterial Immunology [Brussels]
Journal title :
Antimicrobial Agents and Chemotherapy
Pages :
2100-2109
Publisher :
American Society for Microbiology
Publication date :
2009-05
ISSN :
0066-4804
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
ABSTRACT The emergence of Mycobacterium tuberculosis resistant to first-line antibiotics has renewed interest in second-line antitubercular agents. Here, we aimed to extend our understanding of the mechanisms underlying ...
Show more >ABSTRACT The emergence of Mycobacterium tuberculosis resistant to first-line antibiotics has renewed interest in second-line antitubercular agents. Here, we aimed to extend our understanding of the mechanisms underlying para-aminosalicylic acid (PAS) resistance by analysis of six genes of the folate metabolic pathway and biosynthesis of thymine nucleotides ( thyA, dfrA, folC, folP1, folP2 , and thyX ) and three N -acetyltransferase genes [ nhoA, aac(1) , and aac(2) ] among PAS-resistant clinical isolates and spontaneous mutants. Mutations in thyA were identified in only 37% of the clinical isolates and spontaneous mutants. Overall, 24 distinct mutations were identified in the thyA gene and 3 in the dfrA coding region. Based on structural bioinformatics techniques, the altered ThyA proteins were predicted to generate an unfolded or dysfunctional polypeptide. The MIC was determined by Bactec/Alert and dilution assay. Sixty-three percent of the PAS-resistant isolates had no mutations in the nine genes considered in this study, revealing that PAS resistance in M. tuberculosis involves mechanisms or targets other than those pertaining to the biosynthesis of thymine nucleotides. The alternative mechanism(s) or pathway(s) associated with PAS resistance appears to be PAS concentration dependent, in marked contrast to thyA -mutated PAS-resistant isolates.Show less >
Show more >ABSTRACT The emergence of Mycobacterium tuberculosis resistant to first-line antibiotics has renewed interest in second-line antitubercular agents. Here, we aimed to extend our understanding of the mechanisms underlying para-aminosalicylic acid (PAS) resistance by analysis of six genes of the folate metabolic pathway and biosynthesis of thymine nucleotides ( thyA, dfrA, folC, folP1, folP2 , and thyX ) and three N -acetyltransferase genes [ nhoA, aac(1) , and aac(2) ] among PAS-resistant clinical isolates and spontaneous mutants. Mutations in thyA were identified in only 37% of the clinical isolates and spontaneous mutants. Overall, 24 distinct mutations were identified in the thyA gene and 3 in the dfrA coding region. Based on structural bioinformatics techniques, the altered ThyA proteins were predicted to generate an unfolded or dysfunctional polypeptide. The MIC was determined by Bactec/Alert and dilution assay. Sixty-three percent of the PAS-resistant isolates had no mutations in the nine genes considered in this study, revealing that PAS resistance in M. tuberculosis involves mechanisms or targets other than those pertaining to the biosynthesis of thymine nucleotides. The alternative mechanism(s) or pathway(s) associated with PAS resistance appears to be PAS concentration dependent, in marked contrast to thyA -mutated PAS-resistant isolates.Show less >
Language :
Anglais
Peer reviewed article :
Oui
Audience :
Internationale
Popular science :
Non
Source :
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