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RbpA and σ B association regulates polyphosphate levels to modulate mycobacterial isoniazid‐tolerance
Author(s) -
Wang Zhongwei,
Cumming Bridgette M.,
Mao Chunyou,
Zhu Yan,
Lu Pei,
Steyn Adrie J.C.,
Chen Shiyun,
Hu Yangbo
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.13952
Subject(s) - isoniazid , biology , polyphosphate , association (psychology) , microbiology and biotechnology , tuberculosis , biochemistry , pathology , medicine , philosophy , phosphate , epistemology
Summary To facilitate survival under drug stresses, a small population of Mycobacterium tuberculosis can tolerate bactericidal concentrations of drugs without genetic mutations. These drug‐tolerant mycobacteria can be induced by environmental stresses and contribute to recalcitrant infections. However, mechanisms underlying the development of drug‐tolerant mycobacteria remain obscure. Herein, we characterized a regulatory pathway which is important for the tolerance to isoniazid (INH) in Mycobacterium smegmatis . We found that the RNA polymerase binding protein RbpA associates with the stress response sigma factor σ B , to activate the transcription of ppk1 , the gene encoding polyphosphate kinase. Subsequently, intracellular levels of inorganic polyphosphate increase to promote INH‐tolerant mycobacteria. Interestingly, σ B and ppk1 expression varied proportionately in mycobacterial populations and positively correlated with tolerance to INH in individual mycobacteria. Moreover, sigB and ppk1 transcription are both induced upon nutrient depletion, a condition that stimulates the formation of INH‐tolerant mycobacteria. Over‐expression of ppk1 in rbpA knockdown or sigB deleted strains successfully restored the number of INH‐tolerant mycobacteria under both normal growth and nutrient starved conditions. These data suggest that RbpA and σ B regulate ppk1 expression to control drug tolerance both during the logarithmic growth phase and under the nutrition starved conditions.