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Alteration of Metabolic Program by whiB6 Enhances Tuberculosis Persistence
Author(s) -
Jacobs William,
Weinrick Brian
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.222.3
Subject(s) - regulon , multidrug tolerance , isoniazid , biology , tuberculosis , drug resistance , drug , mutant , mycobacterium tuberculosis , drug tolerance , population , transcriptome , microbiology and biotechnology , gene , pharmacology , medicine , gene expression , genetics , bacteria , pathology , environmental health , biofilm
Persisters, drug sensitive survivors of drug treatment, may be the basis of the need for lengthy treatment regimens to cure tuberculosis and could also contribute to the ability of the bacteria to establish a latent infection. We established a basic model of persistence by treating M. tuberculosis cells with isoniazid, an antibiotic that induces lytic cell death. After four days exposure 99.9% of the initial inoculum is killed and the remaining population is significantly enriched in persisters. The transcriptional profile of these persister cells was compared to untreated cells. The most differentially expressed gene not also affected by short‐term isoniazid treatment was a putative transcription factor, whiB6 . We created whiB6 knock out and complemented strains and identified the whiB6 regulon by transcriptional profiling. The whiB6 regulon is composed of genes involved in lipid anabolism, energy metabolism, and adaptation to hypoxia, heat shock, and oxidative stresses. The whiB6 mutant displayed drug tolerance alterations only under conditions simulating in vivo growth. We investigated the behavior of the whiB6 mutant in a mouse model of drug treatment, latency, and reactivation. The mutant was more effectively killed by drug treatment and may be less likely to enter a latent state.