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Regulatory genes coordinating antibiotic‐induced changes in promoter activity and early transcriptional termination of the mycobacterial intrinsic resistance gene whiB7
Author(s) -
Burian Ján,
Thompson Charles J.
Publication year - 2018
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.13890
Subject(s) - mycobacterium smegmatis , biology , gene , antibiotics , mycobacterium tuberculosis , antibiotic resistance , genetics , tetr , mycobacterium , microbiology and biotechnology , gene expression , regulation of gene expression , mutagenesis , transcriptional regulation , mutant , bacteria , repressor , tuberculosis , medicine , pathology
Summary Diseases caused by various Mycobacterium sp ., especially Mycobacterium tuberculosis , are a major burden on global health care. Due to high intrinsic antibiotic resistance, treatment options are severely limited. In mycobacteria, WhiB7 coordinates intrinsic resistance to a broad range of antibiotics. While WhiB7 has been established as an auto‐regulatory transcriptional activator, the signals and genes needed to induce its expression are poorly understood. Using Mycobacterium smegmatis as a model, we coupled transposon mutagenesis and next generation sequencing with WhiB7‐specific antibiotic selection to identify genes that contribute to WhiB7 regulation and function. We showed that whiB7 expression was regulated by two coordinated processes: early termination of the whiB7 transcript and increased whiB7 promoter activity. Early termination was irreversibly maintained by constitutive expression of a putative aspartate aminotransferase gene, MSMEG_4060 . A pair of hypothetical genes, MSMEG_3637 and MSMEG_3638 , were identified as important contributors to whiB7 promoter induction on antibiotic challenge. Expansion of our understanding of the WhiB7‐resistance pathway may lead to identification of inhibitors that allow the use of previously ineffective antibiotics to treat mycobacterial diseases.