RESUMO
The global epidemic of drug-resistant tuberculosis is a catastrophic example of how antimicrobial resistance is undermining the public health gains made possible by combination drug therapy. Recent evidence points to unappreciated bacterial factors that accelerate the emergence of drug resistance. In a genome-wide association study of Mycobacterium tuberculosis isolates from China, we find mutations in the gene encoding the transcription factor prpR enriched in drug-resistant strains. prpR mutations confer conditional drug tolerance to three of the most effective classes of antibiotics by altering propionyl-CoA metabolism. prpR-mediated drug tolerance is carbon-source dependent, and while readily detectable during infection of human macrophages, is not captured by standard susceptibility testing. These data define a previously unrecognized and clinically prevalent class of M. tuberculosis variants that undermine antibiotic efficacy and drive drug resistance.
Assuntos
Proteínas de Bactérias/genética , Farmacorresistência Bacteriana Múltipla/genética , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/genética , Propionatos/metabolismo , Tuberculose Resistente a Múltiplos Medicamentos/genética , Acil Coenzima A/metabolismo , Antituberculosos/farmacologia , China , Estudo de Associação Genômica Ampla , Humanos , Isoniazida/farmacologia , Macrófagos/imunologia , Macrófagos/microbiologia , Mutação/genética , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/metabolismoRESUMO
Monitoring of active polyomavirus BK (BKV) infections by quantitative real-time PCR is becoming a progressively more routine practice in the care of renal transplant patients due to the potential for these infections to injure transplanted kidneys. Quantitative BKV results from a previously validated, laboratory-developed real-time PCR assay based on commercially available MGB Alert reagents were compared to results obtained from the same urine and plasma specimens using a commercially designed real-time PCR assay by IntelligentMDx. When compared qualitatively, the two assays performed identically with the exception of one urine specimen in which BKV DNA was detected near the lower limit of quantification by the MGB Alert assay. A quantitative comparison of the results showed an average 0.55 log(10) copies/mL difference between the two assays. These findings suggest that despite small differences, the IntelligentMDx assay could be adopted for clinical BKV monitoring of renal transplant patients.