Deletion of sigB Causes Increased Sensitivity to para -Aminosalicylic Acid and Sulfamethoxazole in Mycobacterium tuberculosis

Although thede novo folate biosynthesis pathway has been well studied in bacteria, little is known about its regulation. In the present study, thesigB gene inMycobacterium tuberculosis was deleted. Subsequent drug susceptibility tests revealed that theM. tuberculosis ΔsigB strain was more sensitive topara -aminosalicylic acid (PAS) and sulfamethoxazole. Comparative transcriptional analysis was performed, and downregulation ofpabB was observed in the ΔsigB strain, which was further verified by a quantitative reverse transcription-PCR and Western blot assay. Then, the production levels ofpara -aminobenzoic acid (p ABA) were compared between thesigB deletion mutant and wild-type strain, and the results showed thatsigB deletion resulted in decreased production ofp ABA. In addition, SigB was able to recognize the promoter ofpabB in vitro . Furthermore, we found that deletingpabC also caused increased susceptibility to PAS. Taken together, our data revealed that, inM. tuberculosis ,sigB affects susceptibility to antifolates through multiple ways, primarily by regulating the expression ofpabB . To our knowledge, this is the first report showing that SigB modulatesp ABA biosynthesis and thus affecting susceptibility to antifolates, which broadens our understanding of the regulation of bacterial folate metabolism and mechanisms of susceptibility to antifolates.