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Antimicrobial Agents and Chemotherapy, May 2009, p. 2100-2109, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01197-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Molecular Genetics of para-Aminosalicylic Acid Resistance in Clinical Isolates and Spontaneous Mutants of Mycobacterium tuberculosis{triangledown} ,{dagger}

Vanessa Mathys,1,5 René Wintjens,4,5 Philippe Lefevre,1 Julie Bertout,2 Amit Singhal,1 Mehdi Kiass,1 Natalia Kurepina,3 Xiao-Ming Wang,1 Barun Mathema,3 Alain Baulard,2 Barry N. Kreiswirth,3 and Pablo Bifani1*

Laboratory of Molecular Pathology of Tuberculosis, Pasteur Institute, Scientific Institute of Public Health, Brussels, Belgium,1 Inserm U629, Pasteur Institute, Lille, France,2 Tuberculosis Center, Public Health Research Institute, University of Medicine and Dentistry, Newark, New Jersey, 07103,3 Laboratoire de Chimie Générale, Institute of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium,4 Fond National de la Recherche Scientifique (FNRS), Brussels, Belgium5

Received 9 September 2008/ Returned for modification 16 October 2008/ Accepted 12 February 2009

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.

* Corresponding author. Present address: Novartis Institute for Tropical Diseases (NITD), TB Unit, 10 Biopolis Road, 05-01 Chromos, Singapore 138670, Singapore. Phone: 6567223526. Fax: 6567222917. E-mail: Pablo.bifani{at}novartis.com

{triangledown} Published ahead of print on 23 February 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, May 2009, p. 2100-2109, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01197-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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