气候变化领域集成服务门户(CCPortal): Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance

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DOI	10.1073/pnas.1907631116
	Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance
	Safi H.; Gopal P.; Lingaraju S.; Ma S.; Levine C.; Dartois V.; Yee M.; Li L.; Blanc L.; Liang H.-P.H.; Husain S.; Hoque M.; Soteropoulos P.; Rustad T.; Sherman D.R.; Dick T.; Alland D.
发表日期	2019
ISSN	0027-8424
起始页码	19665
结束页码	19674
卷号	116 期号:39
英文摘要	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 7CHT 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. © 2019 National Academy of Sciences. All rights reserved.
英文关键词	GlpK; Mycobacterium tuberculosis; Phase variation; Reversible drug tolerance; Small colony variant
语种	英语
scopus关键词	cytosine; ethambutol; isoniazid; moxifloxacin; rifampicin; animal experiment; animal model; animal tissue; antibiotic sensitivity; Article; bacterial gene; controlled study; dosR gene; drug tolerance; female; frameshift mutation; gene deletion; gene insertion; gene repression; genetic association; glpK gene; in vitro study; kstR gene; lung tuberculosis; minimum inhibitory concentration; mouse; Mycobacterium tuberculosis; nonhuman; phenotype; priority journal; regulon; sigH gene; treatment duration
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/160348
作者单位	Safi, H., Center for Emerging Pathogens, New Jersey Medical School, Rutgers University, Newark, NJ 07103, United States, Department of Medicine, New Jersey Medical School, Rutgers University, Newark, NJ 07103, United States; Gopal, P., Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore, MSD Translational Medicine Research Centre, MSD International GMBH, Singapore, 637766, Singapore; Lingaraju, S., Center for Emerging Pathogens, New Jersey Medical School, Rutgers University, Newark, NJ 07103, United States, Department of Medicine, New Jersey Medical School, Rutgers University, Newark, NJ 07103, United States; Ma, S., Center for Infectious Disease, Seattle Children's Hospital, Seattle, WA 98105, United States; Levine, C., Center for Emerging Pathogens, New Jersey Medical School, Rutgers University, Newark, NJ 07103, United States, Department of Medicine, New Jersey Medical School, Rutgers University, Newark, NJ 07103, United States;...
推荐引用方式 GB/T 7714	Safi H.,Gopal P.,Lingaraju S.,et al. Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance[J],2019,116(39).
APA	Safi H..,Gopal P..,Lingaraju S..,Ma S..,Levine C..,...&Alland D..(2019).Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance.Proceedings of the National Academy of Sciences of the United States of America,116(39).
MLA	Safi H.,et al."Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance".Proceedings of the National Academy of Sciences of the United States of America 116.39(2019).