BACKGROUND: Understanding how growth state influences Mycobacterium tuberculosis responses to antibiotic exposure provides a window into drug action during patient chemotherapy. In this article, we describe the transcriptional programs mediated by isoniazid (INH) during the transition from log-phase to nonreplicating bacilli, from INH-sensitive to INH-tolerant bacilli respectively, using the Wayne model. RESULTS: INH treatment did not elicit a transcriptional response from nonreplicating bacteria under microarophilic conditions (NRP2), unlike the induction of a robust and well-characterized INH signature in log-phase bacilli. CONCLUSION: The differential regulation (between drug-free NRP2 and log-phase bacilli) of genes directly implicated in INH resistance could not account for the abrogation of INH killing in nongrowing bacilli. Thus, factors affecting the requirement for mycolic acids and the redox status of bacilli are likely responsible for the reduction in INH efficacy. We speculate on additional mechanisms revealed by transcriptome analysis that might account for INH tolerance.
BACKGROUND: Understanding how growth state influences Mycobacterium tuberculosis responses to antibiotic exposure provides a window into drug action during patient chemotherapy. In this article, we describe the transcriptional programs mediated by isoniazid (INH) during the transition from log-phase to nonreplicating bacilli, from INH-sensitive to INH-tolerant bacilli respectively, using the Wayne model. RESULTS: INH treatment did not elicit a transcriptional response from nonreplicating bacteria under microarophilic conditions (NRP2), unlike the induction of a robust and well-characterized INH signature in log-phase bacilli. CONCLUSION: The differential regulation (between drug-free NRP2 and log-phase bacilli) of genes directly implicated in INH resistance could not account for the abrogation of INH killing in nongrowing bacilli. Thus, factors affecting the requirement for mycolic acids and the redox status of bacilli are likely responsible for the reduction in INH efficacy. We speculate on additional mechanisms revealed by transcriptome analysis that might account for INH tolerance.
Authors: D G Niranjala Muttucumaru; Gretta Roberts; Jason Hinds; Richard A Stabler; Tanya Parish Journal: Tuberculosis (Edinb) Date: 2004 Impact factor: 3.131
Authors: Manzour Hernando Hazbón; Michael Brimacombe; Miriam Bobadilla del Valle; Magali Cavatore; Marta Inírida Guerrero; Mandira Varma-Basil; Helen Billman-Jacobe; Caroline Lavender; Janet Fyfe; Lourdes García-García; Clara Inés León; Mridula Bose; Fernando Chaves; Megan Murray; Kathleen D Eisenach; José Sifuentes-Osornio; M Donald Cave; Alfredo Ponce de León; David Alland Journal: Antimicrob Agents Chemother Date: 2006-08 Impact factor: 5.191
Authors: M Wilson; J DeRisi; H H Kristensen; P Imboden; S Rane; P O Brown; G K Schoolnik Journal: Proc Natl Acad Sci U S A Date: 1999-10-26 Impact factor: 11.205
Authors: Tobias Hampshire; Shamit Soneji; Joanna Bacon; Brian W James; Jason Hinds; Ken Laing; Richard A Stabler; Philip D Marsh; Philip D Butcher Journal: Tuberculosis (Edinb) Date: 2004 Impact factor: 3.131
Authors: Amit Singh; David K Crossman; Deborah Mai; Loni Guidry; Martin I Voskuil; Matthew B Renfrow; Adrie J C Steyn Journal: PLoS Pathog Date: 2009-08-14 Impact factor: 6.823
Authors: Natalie J Garton; Simon J Waddell; Anna L Sherratt; Su-Min Lee; Rebecca J Smith; Claire Senner; Jason Hinds; Kumar Rajakumar; Richard A Adegbola; Gurdyal S Besra; Philip D Butcher; Michael R Barer Journal: PLoS Med Date: 2008-04-01 Impact factor: 11.069
Authors: Nicholas D Walter; Gregory M Dolganov; Benjamin J Garcia; William Worodria; Alfred Andama; Emmanuel Musisi; Irene Ayakaka; Tran T Van; Martin I Voskuil; Bouke C de Jong; Rebecca M Davidson; Tasha E Fingerlin; Katerina Kechris; Claire Palmer; Payam Nahid; Charles L Daley; Mark Geraci; Laurence Huang; Adithya Cattamanchi; Michael Strong; Gary K Schoolnik; John Lucian Davis Journal: J Infect Dis Date: 2015-03-11 Impact factor: 5.226
Authors: Isobella Honeyborne; Timothy D McHugh; Iitu Kuittinen; Anna Cichonska; Dimitrios Evangelopoulos; Katharina Ronacher; Paul D van Helden; Stephen H Gillespie; Delmiro Fernandez-Reyes; Gerhard Walzl; Juho Rousu; Philip D Butcher; Simon J Waddell Journal: BMC Med Date: 2016-04-07 Impact factor: 8.775
Authors: Obolbek Turapov; Simon J Waddell; Bernard Burke; Sarah Glenn; Asel A Sarybaeva; Griselda Tudo; Gilles Labesse; Danielle I Young; Michael Young; Peter W Andrew; Philip D Butcher; Martin Cohen-Gonsaud; Galina V Mukamolova Journal: Antimicrob Agents Chemother Date: 2014-03-03 Impact factor: 5.191