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Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance

dc.contributor.authorSAFI, Hassan
dc.contributor.authorGOPAL, Pooja
dc.contributor.authorLINGARAJU, Subramanya
dc.contributor.authorMA, Shuyi
dc.contributor.authorLEVINE, Carly
hal.structure.identifierPublic Health Research Institute [Newark] [PHRI]
dc.contributor.authorDARTOIS, Veronique
dc.contributor.authorYEE, Michelle
dc.contributor.authorLI, Liping
hal.structure.identifierPublic Health Research Institute [Newark] [PHRI]
dc.contributor.authorBLANC, Landry
dc.contributor.authorHO LIANG, Hsin-Pin
dc.contributor.authorHUSAIN, Seema
dc.contributor.authorHOQUE, Mainul
hal.structure.identifierCenter for Applied Genomics - Public Health Research Institute
dc.contributor.authorSOTEROPOULOS, Patricia
dc.contributor.authorRUSTAD, Tige
hal.structure.identifierfrom patterns to models in computational biodiversity and biotechnology [PLEIADE]
dc.contributor.authorSHERMAN, David
hal.structure.identifierSouthern Cross University [SCU]
dc.contributor.authorDICK, Thomas
hal.structure.identifierRutgers University [Newark]
dc.contributor.authorALLAND, David
dc.date.issued2019-09-24
dc.identifier.issn0027-8424
dc.description.abstractEnThe 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.
dc.language.isoen
dc.publisherNational Academy of Sciences
dc.title.enPhase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance
dc.typeArticle de revue
dc.identifier.doi10.1073/pnas.1907631116
dc.subject.halSciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire/Biologie moléculaire
bordeaux.journalProceedings of the National Academy of Sciences of the United States of America
bordeaux.page19665-19674
bordeaux.volume116
bordeaux.issue39
bordeaux.peerReviewedoui
hal.identifierhal-04248663
hal.version1
hal.popularnon
hal.audienceInternationale
hal.origin.linkhttps://hal.archives-ouvertes.fr//hal-04248663v1
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