Abstract
Tuberculosis, caused by the pathogen Mycobacterium tuberculosis, is a serious infectious disease worldwide. Multidrug-resistant TB (MDR-TB) remains a global problem, and the understanding of this resistance is incomplete. Studies suggested that DNA methylation promotes bacterial adaptability to antibiotic treatment, but the role of mycobacterial HsdM in drug susceptibility has not been explored. Here, we constructed an inactivated Mycobacterium bovis (BCG) strain, ΔhsdM. ΔhsdM shows growth advantages over wild-type BCG under isoniazid treatment and hypoxia-induced stress. Using high-precision PacBio single-molecule real-time sequencing to compare the ΔhsdM and BCG methylomes, we identified 219 methylated HsdM substrates. Bioinformatics analysis showed that most HsdM-modified genes were enriched in respiration- and energy-related pathways. qPCR showed that HsdM-modified genes directly affected their own transcription, indicating an altered redox regulation. The use of the latent Wayne model revealed that ΔhsdM had growth advantages over wild-type BCG and that HsdM regulated trcR mRNA levels, which may be crucial in regulating transition from latency to reactivation. We found that HsdM regulated corresponding transcription levels via gene methylation; thus, altering the mycobacterial redox status and decreasing the bacterial susceptibility to isoniazid, which is closely correlated with the redox status. Our results provide valuable insight into DNA methylation on drug susceptibility.
Highlights
Tuberculosis (TB) is a chronic wasting infectious disease that causes infections of various tissues and organs after Mycobacterium tuberculosis (Mtb) is inhaled, and spreads through the respiratory tract
Our results showed that HsdM regulated the corresponding transcription levels via gene methylation, leading to changes in the mycobacterial redox status, thereby affecting mycobacterial susceptibility to INH, which was closely correlated with the mycobacterial redox status
We explored the biological functions of the MTase, HsdM, in BCG and showed that deleting hsdM decreased mycobacterial susceptibility to INH and increased mycobacterial survival under hypoxia in BCG
Summary
Tuberculosis (TB) is a chronic wasting infectious disease that causes infections of various tissues and organs after Mycobacterium tuberculosis (Mtb) is inhaled, and spreads through the respiratory tract. According to the Global Tuberculosis Report issued by the World Health Organization in 2019 [1], the number of TB-infected patients has been relatively stable in recent years, with approximately 10 million new cases annually worldwide. Under continued chemotherapy, a fraction of Mtb eventually develops complete antibiotic resistance [4]. It remains unclear how this genetically stable organism adapts so quickly to antibiotic treatments and infected host’s immune pressures such as reactive oxygen species, which are products of the host’s innate immune responses induced by infected Mtb [5]
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