DfrA thyA Double Deletion in para-Aminosalicylic Acid-Resistant Mycobacterium tuberculosis Beijing Strains.
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SUBMITTER: Moradigaravand D
PROVIDER: S-EPMC4879365 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
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dfrA thyA Double Deletion in para-Aminosalicylic Acid-Resistant Mycobacterium tuberculosis Beijing Strains.
Moradigaravand Danesh D Grandjean Louis L Martinez Elena E Li Hao H Zheng Jun J Coronel Jorge J Moore David D Török M Estée ME Sintchenko Vitali V Huang Hairong H Javid Babak B Parkhill Julian J Peacock Sharon J SJ Köser Claudio U CU
Antimicrobial agents and chemotherapy 20160523 6
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Project description:Purpose:The aim of this study is to investigate para-aminosalicylic acid (PAS) resistance-related gene mutations in clinical Mycobacterium tuberculosis (MTB) isolates and analyze the associated risk factors in southwestern China. Patients and methods:Total 122 PAS-resistant and 55 PAS-susceptible clinical isolates were obtained from Chongqing Public Health Medical Center between April 2014 and January 2018. Drug susceptibility test was performed, and the PAS resistance-related genes were sequenced. Results:PAS-resistant strains were more likely to resist streptomycin (OR: 9.5, 95% CI: 3.87-23.3; P<0.01), isoniazid (OR: 5.98, 95% CI: 2.14-16.76; P<0.01), rifampin (OR: 5.01, 95% CI: 2.11-11.88; P<0.01), ethambutol (OR: 2.79, 95% CI: 1.44-5.4; P<0.01), levofloxacin (OR: 2.56, 95% CI: 1.33-4.93; P<0.01), and amikacin (OR: 4.29, 95% CI: 1.70-10.83; P<0.01). The sequencing results showed that 112 (91.8%) PAS-resistant strains harbored 30 different mutations in folC, thyA, and ribD. Mutations in folC were the most commonly observed in PAS-resistant isolates (54.5%, 61/112), followed by mutations in thyA and ribD. Residues I43 in folC, R235 in thyA, and -11G in upstream of ribD were hotspots for mutation sites. Conclusion:PAS drug resistance in MTB in southwestern China is mainly caused by mutations in folC, thyA, and ribD, among which folC was the most frequent mutation. Some mutation hotspots exist in the three genes, which accounts for about 80% of total mutations. These results highlight the possibility of developing molecular diagnostic methods for PAS-resistant tuberculosis in the future.
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Project description:Single nucleotide polymorphisms (SNPs) involved in the development of resistance represent powerful markers for the rapid detection of first- and second-line resistance in clinical Mycobacterium tuberculosis complex (MTBC) isolates. However, the association between particular mutations and phenotypic resistance is not always clear-cut, and phylogenetic SNPs have been misclassified as resistance markers in the past. In the present study, we investigated the utility of a specific polymorphism in thyA (Thr202Ala) as a marker for resistance to para-aminosalicyclic acid (PAS). Sixty-three PAS-susceptible MTBC strains comprising all major phylogenetic lineages, reference strain H37Rv, and 135 multidrug-resistant (MDR) strains from Germany (comprising 8 PAS-resistant isolates) were investigated for the presence of Thr202Ala. In both strain collections, the Thr202Ala SNP was found exclusively in strains of the Latin American Mediterranean (LAM) lineage irrespective of PAS resistance. Furthermore, PAS MICs (0.5 mg/liter) for selected LAM strains (all containing the SNP) and non-LAM strains (not containing the SNP), as well as the results of growth curve analyses performed in liquid 7H9 medium in the presence of increasing PAS concentrations (0 to 2.0 mg/liter), were identical. In conclusion, our data demonstrate that the Thr202Ala polymorphism in thyA is not a valid marker for PAS resistance but, instead, represents a phylogenetic marker for the LAM lineage of the M. tuberculosis complex. These findings challenge some of the previous understanding of PAS resistance and, as a consequence, warrant further in-depth investigations of the genetic variation in PAS-resistant clinical isolates and spontaneous mutants.
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