Role of gyrB Mutations in Pre-extensively and Extensively Drug-Resistant Tuberculosis in Thai Clinical Isolates
| Autor: | Angkana Chaiprasert, Chanwit Tribuddharat, Areeya Disratthakit, Manoon Leechawengwongs, Iyarit Thaipisuttikul, Therdsak Prammananan, Norio Doi |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Ofloxacin medicine.drug_class Extensively Drug-Resistant Tuberculosis Moxifloxacin 030106 microbiology Antitubercular Agents Aminopyridines Gene Expression Levofloxacin Microbial Sensitivity Tests Drug resistance Gatifloxacin DNA gyrase Microbiology Mycobacterium tuberculosis 03 medical and health sciences Mechanisms of Resistance Ciprofloxacin Drug Resistance Bacterial medicine Humans heterocyclic compounds Pharmacology (medical) Tuberculosis Pulmonary Pharmacology biology Extensively drug-resistant tuberculosis biochemical phenomena metabolism and nutrition bacterial infections and mycoses Thailand Quinolone biology.organism_classification medicine.disease Infectious Diseases Sparfloxacin DNA Gyrase Mutation Fluoroquinolones medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 60:5189-5197 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | DNA gyrase mutations are a major cause of quinolone resistance in Mycobacterium tuberculosis . We therefore conducted the first comprehensive study to determine the diversity of gyrase mutations in pre-extensively drug-resistant (pre-XDR) ( n = 71) and extensively drug-resistant (XDR) ( n = 30) Thai clinical tuberculosis (TB) isolates. All pre-XDR-TB and XDR-TB isolates carried at least one mutation within the quinolone resistance-determining region of GyrA (G88A [1.1%], A90V [17.4%], S91P [1.1%], or D94A/G/H/N/V/Y [72.7%]) or GyrB (D533A [1.1%], N538D [1.1%], or E540D [2.2%]). MIC and DNA gyrase supercoiling inhibition assays were performed to determine the role of gyrase mutations in quinolone resistance. Compared to the MICs against M. tuberculosis H37Rv, the levels of resistance to all quinolones tested in the isolates that carried GyrA-D94G or GyrB-N538D (8- to 32-fold increase) were significantly higher than those in isolates bearing GyrA-D94A or GyrA-A90V (2- to 8-fold increase) ( P < 0.01). Intriguingly, GyrB-E540D led to a dramatic resistance to later-generation quinolones, including moxifloxacin, gatifloxacin, and sparfloxacin (8- to 16-fold increases in MICs and 8.3- to 11.2-fold increases in 50% inhibitory concentrations [IC 50 s]). However, GyrB-E540D caused low-level resistance to early-generation quinolones, including ofloxacin, levofloxacin, and ciprofloxacin (2- to 4-fold increases in MICs and 1.5- to 2.0-fold increases in IC 50 s). In the present study, DC-159a was the most active antituberculosis agent and was little affected by the gyrase mutations described above. Our findings suggest that although they are rare, gyrB mutations have a notable role in quinolone resistance, which may provide clues to the molecular basis of estimating quinolone resistance levels for drug and dose selection. |
| Databáze: | OpenAIRE |
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