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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,9,24]]},"abstract":"<jats:p>\n                    The length and complexity of tuberculosis (TB) therapy, as well as the propensity of\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    to develop drug resistance, are major barriers to global TB control efforts.\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    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\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    caused by transient frameshift mutations in a homopolymeric tract (HT) of 7 cytosines (7C) in the\n                    <jats:italic>glpK<\/jats:italic>\n                    gene. Inactivating frameshift mutations associated with the 7C HT in\n                    <jats:italic>glpK<\/jats:italic>\n                    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\n                    <jats:italic>glpK<\/jats:italic>\n                    HT region. These reversible frameshift mutations in the 7C HT of\n                    <jats:italic>M. tuberculosis glpK<\/jats:italic>\n                    occur in clinical isolates, accumulate in\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    -infected mice with further accumulation during drug treatment, and exhibit a reversible transcriptional profile including induction of\n                    <jats:italic>dosR<\/jats:italic>\n                    and\n                    <jats:italic>sigH<\/jats:italic>\n                    and repression of\n                    <jats:italic>kstR<\/jats:italic>\n                    regulons, similar to that observed in other in vitro models of\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    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\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    may hasten TB treatment and improve cure rates.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1907631116","type":"journal-article","created":{"date-parts":[[2019,9,5]],"date-time":"2019-09-05T17:44:06Z","timestamp":1567705446000},"page":"19665-19674","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":160,"title":["Phase variation in\n                    <i>Mycobacterium tuberculosis glpK<\/i>\n                    produces transiently heritable drug tolerance"],"prefix":"10.1073","volume":"116","author":[{"given":"Hassan","family":"Safi","sequence":"first","affiliation":[{"name":"Center for Emerging Pathogens, New Jersey Medical School, Rutgers University, Newark, NJ 07103;"},{"name":"Department of Medicine, New Jersey Medical School, Rutgers University, Newark, NJ 07103;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Gopal","sequence":"additional","affiliation":[{"name":"Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Republic of Singapore;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subramanya","family":"Lingaraju","sequence":"additional","affiliation":[{"name":"Center for Emerging Pathogens, New Jersey Medical School, Rutgers University, Newark, NJ 07103;"},{"name":"Department of Medicine, New Jersey Medical School, Rutgers University, Newark, NJ 07103;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyi","family":"Ma","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease, Seattle Children\u2019s Hospital, Seattle, WA 98105;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carly","family":"Levine","sequence":"additional","affiliation":[{"name":"Center for Emerging 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