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Although  para -aminosalicylic acid (PAS) has been used to treat tuberculosis agent for decades, its mechanisms of resistance are still not thoroughly understood. Previously, sporadic studies showed that certain mutations in the  thyX-hsdS.1  region caused PAS resistance in  M. tuberculosis , but a comprehensive analysis is lacking. Recently, we found a G–10A mutation in  thyX-hsdS.1  in a PAS-resistant clinical isolate, but it did not cause PAS resistance. SNPs in  thyX-hsdS.1  in 6550 clinical isolates were analyzed, and 153 SNPs were identified. C–16 T was the most common SNP identified (54.25%, 83/153), followed by C–4T (7.19%, 11/153) and G–9A (6.54%, 10/153). Subsequently, the effects of those SNPs on the promoter activity of  thyX  were tested, and the results showed that mutations C–1T, G–3A, C–4T, C–4G, G–7A, G–9A, C–16T, G–18C, and C–19G led to increased promoter activity compared with the wild-type sequence, but other mutations did not. Then,  thyX  and wild-type  thyX-hsdS.1 , or  thyX-hsdS.1  containing specific SNPs, were overexpressed in  M. tuberculosis  H37Ra. The results showed that mutations resulting in increased promoter activity also caused PAS resistance. Moreover, the results of an electrophoretic mobility shift assay showed that  thyX-hsdS.1  containing the C–16T mutation had a higher binding capacity to RNA polymerase than did the wild-type sequence. Taken together, our data demonstrated that among the SNPs identified in  thyX-hsdS.1  of  M. tuberculosis  clinical isolates, only those able to increase the promoter activity of  thyX  caused PAS resistance and therefore can be considered as molecular markers for PAS resistance.

Association between mutations in a thyX-hsdS.1 region and para -aminosalicylic acid resistance in Mycobacterium tuberculosis clinical isolates