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Transcriptional adaptation of drug-tolerant Mycobacterium tuberculosis during treatment of human tuberculosis

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dc.contributor.author Walter, N. D.
dc.contributor.author Dolganov, G. M.
dc.contributor.author Garcia, B. J.
dc.contributor.author Worodria, W.
dc.contributor.author Andama, A.
dc.contributor.author Musisi, E.
dc.contributor.author Ayakaka, I.
dc.contributor.author Van, T. T.
dc.contributor.author Voskuil, M. I.
dc.contributor.author de Jong, B. C.
dc.contributor.author Davidson, R. M.
dc.contributor.author Fingerlin, T. E.
dc.contributor.author Kechris, K.
dc.contributor.author Palmer, C.
dc.contributor.author Nahid, P.
dc.contributor.author Daley, C. L.
dc.contributor.author Geraci, M.
dc.contributor.author Huang, L.
dc.contributor.author Cattamanchi, A.
dc.contributor.author Strong, M.
dc.contributor.author Schoolnik, G. K.
dc.contributor.author Davis, J. L.
dc.date.accessioned 2016-02-04T13:59:44Z
dc.date.available 2016-02-04T13:59:44Z
dc.date.issued 2015
dc.identifier.issn 0022-1899
dc.identifier.doi http://dx.doi.org/10.1093/infdis/jiv149
dc.identifier.other ITG-B10A
dc.identifier.other DBM
dc.identifier.other U-MYCOB
dc.identifier.other JIF
dc.identifier.other DOI
dc.identifier.other PDF
dc.identifier.other Abstract
dc.identifier.other UPD60
dc.identifier.uri http://hdl.handle.net/10390/8669
dc.description.abstract BACKGROUND: Treatment initiation rapidly kills most drug-susceptible Mycobacterium tuberculosis, but a bacterial sub-population tolerates prolonged drug exposure. We evaluated drug-tolerant bacilli in human sputum by comparing mRNA expression of drug-tolerant bacilli that survive the early bactericidal phase with treatment-naive bacilli. METHODS: M. tuberculosis gene expression was quantified via RT-PCR in serial sputa from 17 Ugandans treated for drug-susceptible pulmonary tuberculosis. RESULTS: Within four days, bacterial mRNA abundance declined >98%, indicating rapid killing. Thereafter, the rate of decline slowed >94%, indicating drug tolerance. After 14 days, 16S rRNA transcripts/genome declined 96%, indicating slow growth. Drug-tolerant bacilli displayed marked down-regulation of genes associated with growth, metabolism and lipid synthesis and up-regulation in stress responses and key regulatory categories - including stress-associated sigma factors, transcription factors, and toxin-antitoxin genes. Drug efflux pumps were up-regulated. The isoniazid stress signature was induced by initial drug exposure then disappeared after four days. CONCLUSIONS: Transcriptional patterns suggest that drug-tolerant bacilli in sputum are in a slow-growing, metabolically and synthetically down-regulated state. Absence of the isoniazid stress signature in drug-tolerant bacilli indicates that physiological state influences drug responsiveness in vivo. These results identify novel drug targets that should aid in development of novel shorter TB treatment regimens. en_US
dc.language English en_US
dc.subject Bacterial diseases en_US
dc.subject Tuberculosis en_US
dc.subject Pulmonary en_US
dc.subject Mycobacterium tuberculosis en_US
dc.subject Drug resistance en_US
dc.subject Treatment en_US
dc.subject Adaptation en_US
dc.subject Transcription en_US
dc.subject Gene expression en_US
dc.subject Messenger RNA en_US
dc.subject Quantification en_US
dc.subject Exposure en_US
dc.subject Isoniazid en_US
dc.subject Sputum en_US
dc.subject Uganda en_US
dc.subject Africa, East en_US
dc.title Transcriptional adaptation of drug-tolerant Mycobacterium tuberculosis during treatment of human tuberculosis en_US
dc.type Article en_US
dc.citation.issue 6 en_US
dc.citation.jtitle Journal of Infectious Diseases en_US
dc.citation.volume 212 en_US
dc.citation.pages 990-998 en_US
dc.identifier.pmid http://www.ncbi.nlm.nih.gov/pubmed/25762787
dc.citation.jabbreviation J Infect Dis en_US


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