- Mycobacterial Regulatory Systems Involved in the Regulation of Gene Expression Under Respiration‑Inhibitory Conditions
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Yuna Oh , Ha-Na Lee , Eon-Min Ko , Ji-A Jeong , Sae Woong Park , Jeong-Il Oh
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J. Microbiol. 2023;61(3):297-315. Published online February 27, 2023
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DOI: https://doi.org/10.1007/s12275-023-00026-8
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Mycobacterium tuberculosis is the causative agent of tuberculosis. M. tuberculosis can survive in a dormant state within
the granuloma, avoiding the host-mounting immune attack. M. tuberculosis bacilli in this state show increased tolerance
to antibiotics and stress conditions, and thus the transition of M. tuberculosis to the nonreplicating dormant state acts as
an obstacle to tuberculosis treatment. M. tuberculosis in the granuloma encounters hostile environments such as hypoxia,
nitric oxide, reactive oxygen species, low pH, and nutrient deprivation, etc., which are expected to inhibit respiration of M.
tuberculosis. To adapt to and survive in respiration-inhibitory conditions, it is required for M. tuberculosis to reprogram its
metabolism and physiology. In order to get clues to the mechanism underlying the entry of M. tuberculosis to the dormant
state, it is important to understand the mycobacterial regulatory systems that are involved in the regulation of gene expression
in response to respiration inhibition. In this review, we briefly summarize the information regarding the regulatory
systems implicated in upregulation of gene expression in mycobacteria exposed to respiration-inhibitory conditions. The
regulatory systems covered in this review encompass the DosSR (DevSR) two-component system, SigF partner switching
system, MprBA-SigE-SigB signaling pathway, cAMP receptor protein, and stringent response.
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Citations
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Feng Chen, Yifan Shen, Qianhui Yan, Daishan Zheng, Xiaoli Chen, Longyu Fang, Mengchen Sun, Yuansi Zhang, Maoping Chu, Enhui Yang, Xiu-Feng Huang
Annals of Medicine.2026;[Epub] CrossRef - Recent advances in research on Mycobacterium tuberculosis virulence factors and their role in pathogenesis
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Journal of Microbiology, Immunology and Infection.2025; 58(5): 497. CrossRef - Host Immune Pathways to Mycobacterium tuberculosis Infection
Eun-Jin Park, Insoo Kim, Eun-Kyeong Jo
Journal of Bacteriology and Virology.2024; 54(3): 167. CrossRef - Bacterial Regulatory Mechanisms for the Control of Cellular Processes: Simple Organisms’ Complex Regulation
Jin-Won Lee
Journal of Microbiology.2023; 61(3): 273. CrossRef
- Activation of the SigE-SigB signaling pathway by inhibition of the respiratory electron transport chain and its effect on rifampicin resistance in Mycobacterium smegmatis
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Yuna Oh , Hye-In Lee , Ji-A Jeong , Seonghan Kim , Jeong-Il Oh
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J. Microbiol. 2022;60(9):935-947. Published online August 1, 2022
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DOI: https://doi.org/10.1007/s12275-022-2202-0
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Using a mutant of Mycobacterium smegmatis lacking the major
aa3 cytochrome c oxidase of the electron transport chain
(Δaa3), we demonstrated that inhibition of the respiratory
electron transport chain led to an increase in antibiotic resistance
of M. smegmatis to isoniazid, rifampicin, ethambutol,
and tetracycline. The alternative sigma factors SigB and SigE
were shown to be involved in an increase in rifampicin resistance
of M. smegmatis induced under respiration-inhibitory
conditions. As in Mycobacterium tuberculosis, SigE and SigB
form a hierarchical regulatory pathway in M. smegmatis through
SigE-dependent transcription of sigB. Expression of sigB and
sigE was demonstrated to increase in the Δaa3 mutant, leading
to upregulation of the SigB-dependent genes in the mutant.
The phoU2 (MSMEG_1605) gene implicated in a phosphatesignaling
pathway and the MSMEG_1097 gene encoding a putative
glycosyltransferase were identified to be involved in
the SigB-dependent enhancement of rifampicin resistance observed
for the Δaa3 mutant of M. smegmatis. The significance
of this study is that the direct link between the functionality
of the respiratory electron transport chain and antibiotic resistance
in mycobacteria was demonstrated for the first time
using an electron transport chain mutant rather than inhibitors
of electron transport chain.
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Citations
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Yaqi Cui, Ruilin Lou, Zulpya Mahmut, Fangyu Shi, Jiaqi Zhou, Yaqi Zhu, Zhenzhou Wang, Yifan Chen, Lin Xu, Lin Wang, Biao Dong
Journal of Colloid and Interface Science.2027; 725: 141331. CrossRef - Mo(SO)2 porous nanoparticles achieve effective antibacterial through electron attack on the respiratory chain
Yaqi Cui, Zulpya Mahmut, Yangdong Xie, Fangyu Shi, Jiaqi Zhou, Yaqi Zhu, Ruilin Lou, Zhenzhou Wang, Lin Xu, Lin Wang, Biao Dong
Chemical Engineering Journal.2026; 529: 172994. CrossRef -
Activation of the MprBA two-component system in
Mycobacterium smegmatis
under acidic and respiration-inhibitory conditions and crosstalk between MprA and KdpD
Yun-Kyung Kim, Ye-Jin Lee, Jeong-Il Oh, Patricia A. Champion
Journal of Bacteriology.2026;[Epub] CrossRef - Regulatory mechanism of the SenX3-RegX3 two-component system in Mycobacterium smegmatis: Roles of PhoU in sensing inorganic phosphate levels
Youjin Seung, Ha-Eun Baik, Eun-Jin Park, Jeong-Il Oh
Journal of Biological Chemistry.2025; 301(8): 110435. CrossRef -
Inactivation of cAMP receptor protein (MSMEG_6189) increases isoniazid susceptibility in
Mycobacterium smegmatis
via altered oxidative phosphorylation, elevated ROS production, and loss of
ahpC
Narin Kim, Yuna Oh, Jeong-Il Oh, Tina M. Henkin
Journal of Bacteriology.2025;[Epub] CrossRef - Rel-dependent decrease in the expression of ribosomal protein genes by inhibition of the respiratory electron transport chain in Mycobacterium smegmatis
Na-Kyeong Kim, Jong-Eun Baek, Ye-Jin Lee, Yuna Oh, Jeong-Il Oh
Frontiers in Microbiology.2024;[Epub] CrossRef -
MoaB2, a newly identified transcription factor, binds to σ
A
in
Mycobacterium smegmatis
Barbora Brezovská, Subhash Narasimhan, Michaela Šiková, Hana Šanderová, Tomáš Kovaľ, Nabajyoti Borah, Mahmoud Shoman, Debora Pospíšilová, Viola Vaňková Hausnerová, Dávid Tužinčin, Martin Černý, Jan Komárek, Martina Janoušková, Milada Kambová, Petr Halada,
Journal of Bacteriology.2024;[Epub] CrossRef - Enhanced hypoxanthine utilization for cAMP salvage synthesis efficiently by Arthrobacter sp. CCTCC 2013431 via xanthine oxidase inhibition
Baofeng Chen, Hai Tan, Chang Li, Linbo Li, Zhonghua Zhang, Zhigang Li
Biotechnology Letters.2024; 46(6): 1095. CrossRef - Mycobacterial Regulatory Systems Involved in the Regulation of Gene Expression Under Respiration-Inhibitory Conditions
Yuna Oh, Ha-Na Lee, Eon-Min Ko, Ji-A Jeong, Sae Woong Park, Jeong-Il Oh
Journal of Microbiology.2023; 61(3): 297. CrossRef
- Alanine dehydrogenases in mycobacteria
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Ji-A Jeong , Jeong-Il Oh
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J. Microbiol. 2019;57(2):81-92. Published online January 31, 2019
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DOI: https://doi.org/10.1007/s12275-019-8543-7
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Since NAD(H)-dependent L-alanine dehydrogenase (EC
1.1.4.1; Ald) was identified as one of the major antigens present
in culture filtrates of Mycobacterium tuberculosis, many
studies on the enzyme have been conducted. Ald catalyzes
the reversible conversion of pyruvate to alanine with concomitant
oxidation of NADH to NAD+ and has a homohexameric
quaternary structure. Expression of the ald genes was
observed to be strongly upregulated in M. tuberculosis and
Mycobacterium smegmatis grown in the presence of alanine.
Furthermore, expression of the ald genes in some mycobacteria
was observed to increase under respiration-inhibitory
conditions such as oxygen-limiting and nutrient-starvation
conditions. Upregulation of ald expression by alanine or under
respiration-inhibitory conditions is mediated by AldR, a
member of the Lrp/AsnC family of transcriptional regulators.
Mycobacterial Alds were demonstrated to be the enzymes required
for utilization of alanine as a nitrogen source and to
help mycobacteria survive under respiration-inhibitory conditions
by maintaining cellular NADH/NAD+ homeostasis.
Several inhibitors of Ald have been developed, and their application
in combination with respiration-inhibitory antitubercular
drugs such as Q203 and bedaquiline was recently suggested.
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