Mutations in gidB Confer Low-Level Streptomycin Resistance in Mycobacterium tuberculosis
| Autor: | Helena I. Boshoff, Jong Seok Lee, Laura E. Via, Clifton E. Barry, Hyun Kyung Kwak, Sharon Y. Wong |
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| Rok vydání: | 2011 |
| Předmět: |
Tuberculosis
Microbial Sensitivity Tests medicine.disease_cause Mycobacterium tuberculosis Mechanisms of Resistance RNA Ribosomal 16S medicine Pharmacology (medical) Gene Pharmacology Genetics Mutation biology Strain (biology) Methyltransferases Ribosomal RNA biology.organism_classification medicine.disease Phenotype Anti-Bacterial Agents Infectious Diseases Streptomycin Monte Carlo Method medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 55:2515-2522 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.01814-10 |
| Popis: | The global threat posed by drug-resistant strains of Mycobacterium tuberculosis demands a greater understanding of the genetic basis and molecular mechanisms that govern how such strains develop resistance against various antituberculous drugs. In this report, we examine a new genetic basis for resistance to one of the oldest and most widely used second-line drugs employed in tuberculosis therapy, streptomycin (SM). This marker for SM resistance was first discovered on the basis of genomic data obtained from drug-resistant M. tuberculosis strains collected in Japan, wherein an association was observed between SM resistance and a mutation in gidB , a putative 16S rRNA methyltransferase. By evaluating an isogenic Δ gidB mutant strain constructed from strain H37Rv, we demonstrate the causal role of gidB in conferring a low-level SM-resistant phenotype in M. tuberculosis with a 16-fold increase in the MIC over the parent strain. Among clinical isolates, the modest increase in SM resistance conferred by a gidB mutation leads to an MIC distribution of gidB mutation-containing strains that spans the recommended SM breakpoint concentration currently used in drug susceptibility testing protocols. As such, some gidB mutation-containing isolates are found to be SM sensitive, while others are SM resistant. On the basis of a pharmacodynamic analysis and Monte Carlo simulation, those isolates that are found to be SM sensitive should still respond favorably to SM treatment, while nearly half of those found to be SM resistant will likely respond poorly. This report provides the first microbiological evidence for the contribution of gidB in streptomycin resistance and examines the clinical implications of mutations in the gidB gene. |
| Databáze: | OpenAIRE |
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