Details

Autor(en) / Beteiligte

• Walter, Nicholas D.
• Dolganov, Gregory M.
• Garcia, Benjamin J.
• Worodria, William
• Andama, Alfred
• Musisi, Emmanuel
• Ayakaka, Irene
• Van, Tran T.
• Voskuil, Martin I.
• de Jong, Bouke C.
• Davidson, Rebecca M.
• Fingerlin, Tasha E.
• Kechris, Katerina
• Palmer, Claire
• Nahid, Payam
• Daley, Charles L.
• Geraci, Mark
• Huang, Laurence
• Cattamanchi, Adithya
• Strong, Michael
• Schoolnik, Gary K.
• Davis, John Lucian

Titel

Transcriptional Adaptation of Drug-tolerant Mycobacterium tuberculosis During Treatment of Human Tuberculosis

Ist Teil von

• The Journal of infectious diseases, 2015-09, Vol.212 (6), p.990-998

Ort / Verlag

United States: Oxford University Press

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• Background. Treatment initiation rapidly kills most drug-susceptible Mycobacterium tuberculosis, but a bacterial subpopulation tolerates prolonged drug exposure. We evaluated drug-tolerant bacilli in human sputum by comparing messenger RNA (mRNA) expression of drug-tolerant bacilli that survive the early bactericidal phase with treatment-naive bacilli. Methods. M. tuberculosis gene expression was quantified via reverse-transcription polymerase chain reaction in serial sputa from 17 Ugandans treated for drug-susceptible pulmonary tuberculosis. Results. Within 4 days, bacterial mRNA abundance declined >98%, indicating rapid killing. Thereafter, the rate of decline slowed >94%, indicating drug tolerance. After 14 days, 16S ribosomal RNA transcripts/genome declined 96%, indicating slow growth. Drug-tolerant bacilli displayed marked downregulation of genes associated with growth, metabolism, and lipid synthesis and upregulation in stress responses and key regulatory categories—including stress-associated sigma factors, transcription factors, and toxin-antitoxin genes. Drug efflux pumps were upregulated. The isoniazid stress signature was induced by initial drug exposure, then disappeared after 4 days. Conclusions. Transcriptional patterns suggest that drug-tolerant bacilli in sputum are in a slow-growing, metabolically and synthetically downregulated 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 tuberculosis treatment regimens.