Your browser doesn't support javascript.
loading
Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance.
Safi, Hassan; Gopal, Pooja; Lingaraju, Subramanya; Ma, Shuyi; Levine, Carly; Dartois, Veronique; Yee, Michelle; Li, Liping; Blanc, Landry; Ho Liang, Hsin-Pin; Husain, Seema; Hoque, Mainul; Soteropoulos, Patricia; Rustad, Tige; Sherman, David R; Dick, Thomas; Alland, David.
Afiliación
  • Safi H; Center for Emerging Pathogens, New Jersey Medical School, Rutgers University, Newark, NJ 07103; safiha@njms.rutgers.edu david.alland@rutgers.edu.
  • Gopal P; Department of Medicine, New Jersey Medical School, Rutgers University, Newark, NJ 07103.
  • Lingaraju S; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Republic of Singapore.
  • Ma S; Center for Emerging Pathogens, New Jersey Medical School, Rutgers University, Newark, NJ 07103.
  • Levine C; Department of Medicine, New Jersey Medical School, Rutgers University, Newark, NJ 07103.
  • Dartois V; Center for Infectious Disease, Seattle Children's Hospital, Seattle, WA 98105.
  • Yee M; Center for Emerging Pathogens, New Jersey Medical School, Rutgers University, Newark, NJ 07103.
  • Li L; Department of Medicine, New Jersey Medical School, Rutgers University, Newark, NJ 07103.
  • Blanc L; The Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103.
  • Ho Liang HP; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110.
  • Husain S; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Republic of Singapore.
  • Hoque M; The Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103.
  • Soteropoulos P; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110.
  • Rustad T; The Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103.
  • Sherman DR; The Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103.
  • Dick T; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110.
  • Alland D; Genomics Center, New Jersey Medical School, Rutgers University, Newark, NJ 07103.
Proc Natl Acad Sci U S A ; 116(39): 19665-19674, 2019 09 24.
Article en En | MEDLINE | ID: mdl-31488707
The length and complexity of tuberculosis (TB) therapy, as well as the propensity of Mycobacterium tuberculosis to develop drug resistance, are major barriers to global TB control efforts. M. tuberculosis is known to have the ability to enter into a drug-tolerant state, which may explain many of these impediments to TB treatment. We have identified a mechanism of genetically encoded but rapidly reversible drug tolerance in M. tuberculosis caused by transient frameshift mutations in a homopolymeric tract (HT) of 7 cytosines (7C) in the glpK gene. Inactivating frameshift mutations associated with the 7C HT in glpK produce small colonies that exhibit heritable multidrug increases in minimal inhibitory concentrations and decreases in drug-dependent killing; however, reversion back to a fully drug-susceptible large-colony phenotype occurs rapidly through the introduction of additional insertions or deletions in the same glpK HT region. These reversible frameshift mutations in the 7C HT of M. tuberculosis glpK occur in clinical isolates, accumulate in M. tuberculosis-infected mice with further accumulation during drug treatment, and exhibit a reversible transcriptional profile including induction of dosR and sigH and repression of kstR regulons, similar to that observed in other in vitro models of M. tuberculosis tolerance. These results suggest that GlpK phase variation may contribute to drug tolerance, treatment failure, and relapse in human TB. Drugs effective against phase-variant M. tuberculosis may hasten TB treatment and improve cure rates.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tolerancia a Medicamentos / Glicerol Quinasa / Mycobacterium tuberculosis Límite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tolerancia a Medicamentos / Glicerol Quinasa / Mycobacterium tuberculosis Límite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos