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

Although the de novo folate biosynthesis pathway has been well studied in bacteria, little is known about its regulation. In this study, the sigB gene in Mycobacterium tuberculosis (M. tb) was deleted. Subsequent drug susceptibility tests revealed that M. tb sigB was more sensitive to para-aminosalicylic acid (PAS) and sulfamethoxazole (SMX). Comparative transcriptional analysis was performed and down-regulation of pabB was observed in the sigB deleted strain, which was further verified by qRT-PCR and Western blot assay. Then production of para-aminobenzoic acid (pABA) were compared between the sigB deletion mutant and wild type strain, and results showed that sigB deletion resulted in decreased production of pABA. Additionally, SigB was found to be able to recognize the promoter of pabB in vitro. Furthermore, we found that deleting pabC also caused increased susceptibility to PAS. Taken together, our data revealed that, in M. tb, sigB affects susceptibility to antifolates through multiple ways, the most of which is regulating the expression of pabB. To our knowledge, this is the first report showing that SigB modulates pABA biosynthesis and thus affecting susceptibility to antifolates, which broadens our understanding of the regulation of bacterial folate metabolism and mechanisms of susceptibility to antifolates.

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