The Mycobacterial DNA Methyltransferase HsdM Decreases Intrinsic Isoniazid Susceptibility

Tuberculosis, caused by the pathogen <i>Mycobacterium tuberculosis</i>, 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 a...

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Autores principales:	Xinling Hu, Xintong Zhou, Tong Yin, Keyu Chen, Yongfei Hu, Baoli Zhu, Kaixia Mi
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	DNA methyltransferase HsdM isoniazid <i>Mycobacterium bovis</i> BCG drug susceptibility Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/5a4e3e3d19f749f49e728f981d6312e9
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spelling	oai:doaj.org-article:5a4e3e3d19f749f49e728f981d6312e92021-11-25T16:22:50ZThe Mycobacterial DNA Methyltransferase HsdM Decreases Intrinsic Isoniazid Susceptibility10.3390/antibiotics101113232079-6382https://doaj.org/article/5a4e3e3d19f749f49e728f981d6312e92021-10-01T00:00:00Zhttps://www.mdpi.com/2079-6382/10/11/1323https://doaj.org/toc/2079-6382Tuberculosis, caused by the pathogen <i>Mycobacterium tuberculosis</i>, 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 <i>Mycobacterium bovis</i> (BCG) strain, Δ<i>hsdM</i>. Δ<i>hsdM</i> 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 Δ<i>hsdM</i> 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 Δ<i>hsdM</i> had growth advantages over wild-type BCG and that HsdM regulated <i>trcR</i> 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.Xinling HuXintong ZhouTong YinKeyu ChenYongfei HuBaoli ZhuKaixia MiMDPI AGarticleDNA methyltransferaseHsdMisoniazid<i>Mycobacterium bovis</i> BCGdrug susceptibilityTherapeutics. PharmacologyRM1-950ENAntibiotics, Vol 10, Iss 1323, p 1323 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNA methyltransferase HsdM isoniazid <i>Mycobacterium bovis</i> BCG drug susceptibility Therapeutics. Pharmacology RM1-950
spellingShingle	DNA methyltransferase HsdM isoniazid <i>Mycobacterium bovis</i> BCG drug susceptibility Therapeutics. Pharmacology RM1-950 Xinling Hu Xintong Zhou Tong Yin Keyu Chen Yongfei Hu Baoli Zhu Kaixia Mi The Mycobacterial DNA Methyltransferase HsdM Decreases Intrinsic Isoniazid Susceptibility
description	Tuberculosis, caused by the pathogen <i>Mycobacterium tuberculosis</i>, 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 <i>Mycobacterium bovis</i> (BCG) strain, Δ<i>hsdM</i>. Δ<i>hsdM</i> 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 Δ<i>hsdM</i> 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 Δ<i>hsdM</i> had growth advantages over wild-type BCG and that HsdM regulated <i>trcR</i> 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.
format	article
author	Xinling Hu Xintong Zhou Tong Yin Keyu Chen Yongfei Hu Baoli Zhu Kaixia Mi
author_facet	Xinling Hu Xintong Zhou Tong Yin Keyu Chen Yongfei Hu Baoli Zhu Kaixia Mi
author_sort	Xinling Hu
title	The Mycobacterial DNA Methyltransferase HsdM Decreases Intrinsic Isoniazid Susceptibility
title_short	The Mycobacterial DNA Methyltransferase HsdM Decreases Intrinsic Isoniazid Susceptibility
title_full	The Mycobacterial DNA Methyltransferase HsdM Decreases Intrinsic Isoniazid Susceptibility
title_fullStr	The Mycobacterial DNA Methyltransferase HsdM Decreases Intrinsic Isoniazid Susceptibility
title_full_unstemmed	The Mycobacterial DNA Methyltransferase HsdM Decreases Intrinsic Isoniazid Susceptibility
title_sort	mycobacterial dna methyltransferase hsdm decreases intrinsic isoniazid susceptibility
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/5a4e3e3d19f749f49e728f981d6312e9
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The Mycobacterial DNA Methyltransferase HsdM Decreases Intrinsic Isoniazid Susceptibility

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