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Article: Mycobacterium tuberculosis H2S Functions as a Sink to Modulate Central Metabolism, Bioenergetics, and Drug Susceptibility

Kunota, Tafara T. R. / Rahman, Md. Aejazur / Truebody, Barry E. / Mackenzie, Jared S. / Saini, Vikram / Lamprecht, Dirk A. / Adamson, John H. / Sevalkar, Ritesh R. / Lancaster, Jack R. / Berney, Michael / Glasgow, Joel N. / Steyn, Adrie J. C.

Antioxidants. 2021 Aug. 13, v. 10, no. 8

2021

Abstract: H₂S is a potent gasotransmitter in eukaryotes and bacteria. Host-derived H₂S has been shown to profoundly alter M. tuberculosis (Mtb) energy metabolism and growth. However, compelling evidence for endogenous production of H₂S and its role in Mtb ... ...

Abstract	H₂S is a potent gasotransmitter in eukaryotes and bacteria. Host-derived H₂S has been shown to profoundly alter M. tuberculosis (Mtb) energy metabolism and growth. However, compelling evidence for endogenous production of H₂S and its role in Mtb physiology is lacking. We show that multidrug-resistant and drug-susceptible clinical Mtb strains produce H₂S, whereas H₂S production in non-pathogenic M. smegmatis is barely detectable. We identified Rv3684 (Cds1) as an H₂S-producing enzyme in Mtb and show that cds1 disruption reduces, but does not eliminate, H₂S production, suggesting the involvement of multiple genes in H₂S production. We identified endogenous H₂S to be an effector molecule that maintains bioenergetic homeostasis by stimulating respiration primarily via cytochrome bd. Importantly, H₂S plays a key role in central metabolism by modulating the balance between oxidative phosphorylation and glycolysis, and it functions as a sink to recycle sulfur atoms back to cysteine to maintain sulfur homeostasis. Lastly, Mtb-generated H₂S regulates redox homeostasis and susceptibility to anti-TB drugs clofazimine and rifampicin. These findings reveal previously unknown facets of Mtb physiology and have implications for routine laboratory culturing, understanding drug susceptibility, and improved diagnostics.
Keywords	Mycobacterium tuberculosis ; cysteine ; diagnostic techniques ; enzymes ; eukaryotic cells ; glycolysis ; homeostasis ; multiple drug resistance ; oxidative phosphorylation ; rifampicin ; sulfur
Language	English
Dates of publication	2021-0813
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox10081285
Database	NAL-Catalogue (AGRICOLA)

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Article: Mycobacterium tuberculosis

Kunota, Tafara T R / Rahman, Md Aejazur / Truebody, Barry E / Mackenzie, Jared S / Saini, Vikram / Lamprecht, Dirk A / Adamson, John H / Sevalkar, Ritesh R / Lancaster, Jack R / Berney, Michael / Glasgow, Joel N / Steyn, Adrie J C

Antioxidants (Basel, Switzerland)

2021 Volume 10, Issue 8

Abstract: ... ...

Abstract	H
Language	English
Publishing date	2021-08-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox10081285
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis.

Mackenzie, Jared S / Lamprecht, Dirk A / Asmal, Rukaya / Adamson, John H / Borah, Khushboo / Beste, Dany J V / Lee, Bei Shi / Pethe, Kevin / Rousseau, Simon / Krieger, Inna / Sacchettini, James C / Glasgow, Joel N / Steyn, Adrie J C

Nature communications

2020 Volume 11, Issue 1, Page(s) 6092

Abstract: The approval of bedaquiline (BDQ) for the treatment of tuberculosis has generated substantial interest in inhibiting energy metabolism as a therapeutic paradigm. However, it is not known precisely how BDQ triggers cell death in Mycobacterium tuberculosis ...

Abstract	The approval of bedaquiline (BDQ) for the treatment of tuberculosis has generated substantial interest in inhibiting energy metabolism as a therapeutic paradigm. However, it is not known precisely how BDQ triggers cell death in Mycobacterium tuberculosis (Mtb). Using
MeSH term(s)	Anti-Bacterial Agents/pharmacology ; Antitubercular Agents/pharmacology ; Bacterial Proteins/metabolism ; Carbon Cycle/drug effects ; Citric Acid Cycle/drug effects ; Diarylquinolines/pharmacology ; Energy Metabolism/drug effects ; Glycolysis/drug effects ; Glyoxylates ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/metabolism ; Oxidative Phosphorylation ; Tuberculosis/microbiology
Chemical Substances	Anti-Bacterial Agents ; Antitubercular Agents ; Bacterial Proteins ; Diarylquinolines ; Glyoxylates ; bedaquiline (78846I289Y) ; glyoxylic acid (JQ39C92HH6)
Language	English
Publishing date	2020-11-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-19959-4
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: New 2-Ethylthio-4-methylaminoquinazoline derivatives inhibiting two subunits of cytochrome bc1 in Mycobacterium tuberculosis.

Lupien, Andréanne / Foo, Caroline Shi-Yan / Savina, Svetlana / Vocat, Anthony / Piton, Jérémie / Monakhova, Natalia / Benjak, Andrej / Lamprecht, Dirk A / Steyn, Adrie J C / Pethe, Kevin / Makarov, Vadim A / Cole, Stewart T

PLoS pathogens

2020 Volume 16, Issue 1, Page(s) e1008270

Abstract: The emergence of multi-drug (MDR-TB) and extensively-drug resistant tuberculosis (XDR-TB) is a major threat to the global management of tuberculosis (TB) worldwide. New chemical entities are of need to treat drug-resistant TB. In this study, the mode of ... ...

Abstract	The emergence of multi-drug (MDR-TB) and extensively-drug resistant tuberculosis (XDR-TB) is a major threat to the global management of tuberculosis (TB) worldwide. New chemical entities are of need to treat drug-resistant TB. In this study, the mode of action of new, potent quinazoline derivatives was investigated against Mycobacterium tuberculosis (M. tb). Four derivatives 11626141, 11626142, 11626252 and 11726148 showed good activity (MIC ranging from 0.02-0.09 μg/mL) and low toxicity (TD50 ≥ 5μg/mL) in vitro against M. tb strain H37Rv and HepG2 cells, respectively. 11626252 was the most selective compound from this series. Quinazoline derivatives were found to target cytochrome bc1 by whole-genome sequencing of mutants selected with 11626142. Two resistant mutants harboured the transversion T943G (Trp312Gly) and the transition G523A (Gly175Ser) in the cytochrome bc1 complex cytochrome b subunit (QcrB). Interestingly, a third mutant QuinR-M1 contained a mutation in the Rieske iron-sulphur protein (QcrA) leading to resistance to quinazoline and other QcrB inhibitors, the first report of cross-resistance involving QcrA. Modelling of both QcrA and QcrB revealed that all three resistance mutations are located in the stigmatellin pocket, as previously observed for other QcrB inhibitors such as Q203, AX-35, and lansoprazole sulfide (LPZs). Further analysis of the mode of action in vitro revealed that 11626252 exposure leads to ATP depletion, a decrease in the oxygen consumption rate and also overexpression of the cytochrome bd oxidase in M. tb. Our findings suggest that quinazoline-derived compounds are a new and attractive chemical entity for M. tb drug development targeting two separate subunits of the cytochrome bc1 complex.
MeSH term(s)	Antitubercular Agents/chemistry ; Antitubercular Agents/pharmacology ; Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Drug Resistance, Bacterial ; Electron Transport Complex III/antagonists & inhibitors ; Electron Transport Complex III/genetics ; Electron Transport Complex III/metabolism ; Humans ; Microbial Sensitivity Tests ; Mutation ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/metabolism ; Quinazolines/chemistry ; Quinazolines/pharmacology ; Tuberculosis, Multidrug-Resistant/drug therapy ; Tuberculosis, Multidrug-Resistant/microbiology
Chemical Substances	2-ethylthio-4-methylaminoquinazoline ; Antitubercular Agents ; Bacterial Proteins ; Quinazolines ; Electron Transport Complex III (EC 7.1.1.8)
Language	English
Publishing date	2020-01-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1008270
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Mycobacterium tuberculosis arrests host cycle at the G1/S transition to establish long term infection.

Cumming, Bridgette M / Rahman, Md Aejazur / Lamprecht, Dirk A / Rohde, Kyle H / Saini, Vikram / Adamson, John H / Russell, David G / Steyn, Adrie J C

PLoS pathogens

2017 Volume 13, Issue 5, Page(s) e1006389

Abstract: Signals modulating the production of Mycobacterium tuberculosis (Mtb) virulence factors essential for establishing long-term persistent infection are unknown. The WhiB3 redox regulator is known to regulate the production of Mtb virulence factors, however ...

Abstract	Signals modulating the production of Mycobacterium tuberculosis (Mtb) virulence factors essential for establishing long-term persistent infection are unknown. The WhiB3 redox regulator is known to regulate the production of Mtb virulence factors, however the mechanisms of this modulation are unknown. To advance our understanding of the mechanisms involved in WhiB3 regulation, we performed Mtb in vitro, intraphagosomal and infected host expression analyses. Our Mtb expression analyses in conjunction with extracellular flux analyses demonstrated that WhiB3 maintains bioenergetic homeostasis in response to available carbon sources found in vivo to establish Mtb infection. Our infected host expression analysis indicated that WhiB3 is involved in regulation of the host cell cycle. Detailed cell-cycle analysis revealed that Mtb infection inhibited the macrophage G1/S transition, and polyketides under WhiB3 control arrested the macrophages in the G0-G1 phase. Notably, infection with the Mtb whiB3 mutant or polyketide mutants had little effect on the macrophage cell cycle and emulated the uninfected cells. This suggests that polyketides regulated by Mtb WhiB3 are responsible for the cell cycle arrest observed in macrophages infected with the wild type Mtb. Thus, our findings demonstrate that Mtb WhiB3 maintains bioenergetic homeostasis to produce polyketide and lipid cyclomodulins that target the host cell cycle. This is a new mechanism whereby Mtb modulates the immune system by altering the host cell cycle to promote long-term persistence. This new knowledge could serve as the foundation for new host-directed therapeutic discovery efforts that target the host cell cycle.
Language	English
Publishing date	2017-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1006389
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Correction: Mycobacterium tuberculosis arrests host cycle at the G1/S transition to establish long term infection.

Cumming, Bridgette M / Rahman, Md Aejazur / Lamprecht, Dirk A / Rohde, Kyle H / Saini, Vikram / Adamson, John H / Russell, David G / Steyn, Adrie J C

PLoS pathogens

2017 Volume 13, Issue 7, Page(s) e1006490

Abstract: This corrects the article DOI: 10.1371/journal.ppat.1006389.]. ...

Abstract	[This corrects the article DOI: 10.1371/journal.ppat.1006389.].
Language	English
Publishing date	2017-07-14
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1006490
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Compromised Metabolic Reprogramming Is an Early Indicator of CD8

Russell, Shannon L / Lamprecht, Dirk A / Mandizvo, Tawanda / Jones, Terrence T / Naidoo, Vanessa / Addicott, Kelvin W / Moodley, Chivonne / Ngcobo, Bongani / Crossman, David K / Wells, Gordon / Steyn, Adrie J C

Cell reports

2019 Volume 29, Issue 11, Page(s) 3564–3579.e5

Abstract: The immunometabolic mechanisms underlying suboptimal T cell immunity in tuberculosis remain undefined. Here, we examine how chronic Mycobacterium tuberculosis (Mtb) and M. bovis BCG infections rewire metabolic circuits and alter effector functions in ... ...

Abstract	The immunometabolic mechanisms underlying suboptimal T cell immunity in tuberculosis remain undefined. Here, we examine how chronic Mycobacterium tuberculosis (Mtb) and M. bovis BCG infections rewire metabolic circuits and alter effector functions in lung CD8
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Cells, Cultured ; Cytokines/metabolism ; Female ; Glycolysis ; Hypoglycemic Agents/pharmacology ; Latent Tuberculosis/immunology ; Latent Tuberculosis/microbiology ; Metformin/pharmacology ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism ; Mycobacterium bovis/pathogenicity ; Mycobacterium tuberculosis/pathogenicity
Chemical Substances	Cytokines ; Hypoglycemic Agents ; Metformin (9100L32L2N)
Language	English
Publishing date	2019-12-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.11.034
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Hydrogen sulfide stimulates Mycobacterium tuberculosis respiration, growth and pathogenesis.

Saini, Vikram / Chinta, Krishna C / Reddy, Vineel P / Glasgow, Joel N / Stein, Asaf / Lamprecht, Dirk A / Rahman, Md Aejazur / Mackenzie, Jared S / Truebody, Barry E / Adamson, John H / Kunota, Tafara T R / Bailey, Shannon M / Moellering, Douglas R / Lancaster, Jack R / Steyn, Adrie J C

Nature communications

2020 Volume 11, Issue 1, Page(s) 557

Abstract: Hydrogen sulfide ( ... ...

Abstract	Hydrogen sulfide (H
MeSH term(s)	Animals ; Copper/metabolism ; Cystathionine beta-Synthase/genetics ; Cystathionine beta-Synthase/metabolism ; Cytokines/blood ; Disease Models, Animal ; Electron Transport Complex IV/metabolism ; Energy Metabolism ; Female ; Gene Expression Regulation, Bacterial/drug effects ; Homeostasis ; Hydrogen Sulfide/pharmacology ; Lung/pathology ; Macrophages ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/metabolism ; Mycobacterium tuberculosis/pathogenicity ; RAW 264.7 Cells ; Regulon ; Sulfur/metabolism ; Transcriptome ; Tuberculosis
Chemical Substances	Cytokines ; Sulfur (70FD1KFU70) ; Copper (789U1901C5) ; Electron Transport Complex IV (EC 1.9.3.1) ; Cystathionine beta-Synthase (EC 4.2.1.22) ; Hydrogen Sulfide (YY9FVM7NSN)
Language	English
Publishing date	2020-01-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-14132-y
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Arylvinylpiperazine Amides, a New Class of Potent Inhibitors Targeting QcrB of Mycobacterium tuberculosis.

Foo, Caroline S / Lupien, Andréanne / Kienle, Maryline / Vocat, Anthony / Benjak, Andrej / Sommer, Raphael / Lamprecht, Dirk A / Steyn, Adrie J C / Pethe, Kevin / Piton, Jérémie / Altmann, Karl-Heinz / Cole, Stewart T

mBio

2018 Volume 9, Issue 5

Abstract: New drugs are needed to control the current tuberculosis (TB) pandemic caused by infection ... ...

Abstract	New drugs are needed to control the current tuberculosis (TB) pandemic caused by infection with
MeSH term(s)	Amides/pharmacology ; Amides/therapeutic use ; Animals ; Antitubercular Agents/pharmacology ; Bacterial Proteins/antagonists & inhibitors ; Cell Line ; Electron Transport Complex III/metabolism ; Female ; Humans ; Macrophages/drug effects ; Macrophages/microbiology ; Mice ; Mice, Inbred BALB C ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis/drug effects ; Piperazines/pharmacology ; Tuberculosis/drug therapy ; Tuberculosis/microbiology
Chemical Substances	Amides ; Antitubercular Agents ; Bacterial Proteins ; Piperazines ; Electron Transport Complex III (EC 7.1.1.8)
Language	English
Publishing date	2018-10-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mBio.01276-18
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: An enzyme-initiated Smiles rearrangement enables the development of an assay of MshB, the GlcNAc-Ins deacetylase of mycothiol biosynthesis.

Lamprecht, Dirk A / Muneri, Ndivhuwo O / Eastwood, Hayden / Naidoo, Kevin J / Strauss, Erick / Jardine, Anwar

Organic & biomolecular chemistry

2012 Volume 10, Issue 27, Page(s) 5278–5288

Abstract: MshB is the N-acetyl-1-D-myo-inosityl-2-amino-2-deoxy-D-glucopyranoside (GlcNAc-Ins) deacetylase active as one of the enzymes involved in the biosynthesis of mycothiol (MSH), a protective low molecular weight thiol present only in Mycobacterium ... ...

Abstract	MshB is the N-acetyl-1-D-myo-inosityl-2-amino-2-deoxy-D-glucopyranoside (GlcNAc-Ins) deacetylase active as one of the enzymes involved in the biosynthesis of mycothiol (MSH), a protective low molecular weight thiol present only in Mycobacterium tuberculosis and other actinomycetes. In this study, structural analogues of GlcNAc-Ins in which the inosityl moiety is replaced by a chromophore were synthesized and evaluated as alternate substrates of MshB, with the goal of identifying a compound that would be useful in high-throughput assays of the enzyme. In an unexpected and surprising finding one of the GlcNAc-Ins analogues is shown to undergo a Smiles rearrangement upon MshB-mediated deacetylation, uncovering a free thiol group. We demonstrate that this chemistry can be exploited for the development of the first continuous assay of MshB activity based on the detection of thiol formation by DTNB (Ellman's reagent); such an assay should be ideally suited for the identification of MshB inhibitors by means of high-throughput screens in microplates.
MeSH term(s)	Amidohydrolases/chemistry ; Amidohydrolases/metabolism ; Bacterial Proteins/chemistry ; Bacterial Proteins/metabolism ; Biocatalysis ; Catalytic Domain ; Cysteine/biosynthesis ; Cysteine/chemistry ; Glycopeptides/biosynthesis ; Glycopeptides/chemistry ; Inositol/biosynthesis ; Inositol/chemistry ; Models, Molecular ; Mycobacterium tuberculosis/enzymology ; Substrate Specificity
Chemical Substances	Bacterial Proteins ; Glycopeptides ; mycothiol ; Inositol (4L6452S749) ; Amidohydrolases (EC 3.5.-) ; N-acetyl-1-D-inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside deacetylase (EC 3.5.1.-) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2012-07-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2097583-1
ISSN	1477-0539 ; 1477-0520
ISSN (online)	1477-0539
ISSN	1477-0520
DOI	10.1039/c2ob25429h
Database	MEDical Literature Analysis and Retrieval System OnLINE

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