DNA Methyltransferase HsdM Induce Drug Resistance on <i>Mycobacterium tuberculosis</i> via Multiple Effects

• Main Authors: Hongqian Chu (Author), Yongfei Hu (Author), Bing Zhang (Author), Zhaogang Sun (Author), Baoli Zhu (Author)
• Format: Book
• Published: MDPI AG, 2021-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Besides the genomic variants, epigenetic mechanisms such as DNA methylation also have an effect on drug resistance. This study aimed to investigate the methylomes of totally/extensively drug-resistant <i>M. tuberculosis</i> clinical isolates using the PacBio single-molecule real-time technology. The results showed they were almost the same as the pan-susceptible ones. Genetics and bioinformatics analysis confirmed three DNA methyltransferases-MamA, MamB, and HsdM. Moreover, anti-tuberculosis drug treatment did not change the methylomes. In addition, the knockout of the DNA methyltransferase <i>hsdM</i> gene in the extensively drug-resistant clinical isolate 11826 revealed that the motifs of GTAYN4ATC modified by HsdM were completely demethylated. Furthermore, the results of the methylated DNA target analysis found that HsdM was mainly involved in redox-related pathways, especially the prodrug isoniazid active protein KatG. HsdM also targeted three drug-targeted genes, <i>eis</i>, <i>embB</i>, and <i>gyrA</i>, and three drug transporters (Rv0194, Rv1410, and Rv1877), which mildly affected the drug susceptibility. The overexpression of HsdM in <i>M. smegmatis</i> increased the basal mutation rate. Our results suggested that DNA methyltransferase HsdM affected the drug resistance of <i>M. tuberculosis</i> by modulating the gene expression of redox, drug targets and transporters, and gene mutation.

Item Description

10.3390/antibiotics10121544
2079-6382