Skip to main content
eScholarship
Open Access Publications from the University of California

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

  • Author(s): Walter, ND
  • Dolganov, GM
  • Garcia, BJ
  • Worodria, W
  • Andama, A
  • Musisi, E
  • Ayakaka, I
  • Van, TT
  • Voskuil, MI
  • De Jong, BC
  • Davidson, RM
  • Fingerlin, TE
  • Kechris, K
  • Palmer, C
  • Nahid, P
  • Daley, CL
  • Geraci, M
  • Huang, L
  • Cattamanchi, A
  • Strong, M
  • Schoolnik, GK
  • Davis, JL
  • et al.

Published Web Location

http://jid.oxfordjournals.org/content/212/6/990.full.pdf+html
No data is associated with this publication.
Abstract

© 2015 The Author 2015. 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.

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Item not freely available? Link broken?
Report a problem accessing this item