<i>Mycobacterium tuberculosis</i> H<sub>2</sub>S Functions as a Sink to Modulate Central Metabolism, Bioenergetics, and Drug Susceptibility
H<sub>2</sub>S is a potent gasotransmitter in eukaryotes and bacteria. Host-derived H<sub>2</sub>S has been shown to profoundly alter <i>M. tuberculosis</i> (<i>Mtb</i>) energy metabolism and growth. However, compelling evidence for endogenous producti...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-08-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/8/1285 |
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| author | Tafara T. R. Kunota Md. Aejazur Rahman Barry E. Truebody Jared S. Mackenzie Vikram Saini Dirk A. Lamprecht John H. Adamson Ritesh R. Sevalkar Jack R. Lancaster Michael Berney Joel N. Glasgow Adrie J. C. Steyn |
| author_facet | Tafara T. R. Kunota Md. Aejazur Rahman Barry E. Truebody Jared S. Mackenzie Vikram Saini Dirk A. Lamprecht John H. Adamson Ritesh R. Sevalkar Jack R. Lancaster Michael Berney Joel N. Glasgow Adrie J. C. Steyn |
| author_sort | Tafara T. R. Kunota |
| collection | DOAJ |
| description | H<sub>2</sub>S is a potent gasotransmitter in eukaryotes and bacteria. Host-derived H<sub>2</sub>S has been shown to profoundly alter <i>M. tuberculosis</i> (<i>Mtb</i>) energy metabolism and growth. However, compelling evidence for endogenous production of H<sub>2</sub>S and its role in <i>Mtb</i> physiology is lacking. We show that multidrug-resistant and drug-susceptible clinical <i>Mtb</i> strains produce H<sub>2</sub>S, whereas H<sub>2</sub>S production in non-pathogenic <i>M. smegmatis</i> is barely detectable. We identified Rv3684 (Cds1) as an H<sub>2</sub>S-producing enzyme in <i>Mtb</i> and show that <i>cds1</i> disruption reduces, but does not eliminate, H<sub>2</sub>S production, suggesting the involvement of multiple genes in H<sub>2</sub>S production. We identified endogenous H<sub>2</sub>S to be an effector molecule that maintains bioenergetic homeostasis by stimulating respiration primarily via cytochrome <i>bd</i>. Importantly, H<sub>2</sub>S 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, <i>Mtb</i>-generated H<sub>2</sub>S regulates redox homeostasis and susceptibility to anti-TB drugs clofazimine and rifampicin. These findings reveal previously unknown facets of <i>Mtb</i> physiology and have implications for routine laboratory culturing, understanding drug susceptibility, and improved diagnostics. |
| first_indexed | 2024-03-10T09:03:54Z |
| format | Article |
| id | doaj.art-fec3048b30624ab090468cbae2579f5b |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T09:03:54Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-fec3048b30624ab090468cbae2579f5b2023-11-22T06:36:56ZengMDPI AGAntioxidants2076-39212021-08-01108128510.3390/antiox10081285<i>Mycobacterium tuberculosis</i> H<sub>2</sub>S Functions as a Sink to Modulate Central Metabolism, Bioenergetics, and Drug SusceptibilityTafara T. R. Kunota0Md. Aejazur Rahman1Barry E. Truebody2Jared S. Mackenzie3Vikram Saini4Dirk A. Lamprecht5John H. Adamson6Ritesh R. Sevalkar7Jack R. Lancaster8Michael Berney9Joel N. Glasgow10Adrie J. C. Steyn11Africa Health Research Institute, University of KwaZulu Natal, Durban 4001, South AfricaAfrica Health Research Institute, University of KwaZulu Natal, Durban 4001, South AfricaAfrica Health Research Institute, University of KwaZulu Natal, Durban 4001, South AfricaAfrica Health Research Institute, University of KwaZulu Natal, Durban 4001, South AfricaDepartment of Biotechnology, All India Institute of Medical Sciences, New Delhi 110029, IndiaAfrica Health Research Institute, University of KwaZulu Natal, Durban 4001, South AfricaAfrica Health Research Institute, University of KwaZulu Natal, Durban 4001, South AfricaDepartment of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Pharmacology and Chemical Biology, Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USADepartment of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY 10462, USADepartment of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USAAfrica Health Research Institute, University of KwaZulu Natal, Durban 4001, South AfricaH<sub>2</sub>S is a potent gasotransmitter in eukaryotes and bacteria. Host-derived H<sub>2</sub>S has been shown to profoundly alter <i>M. tuberculosis</i> (<i>Mtb</i>) energy metabolism and growth. However, compelling evidence for endogenous production of H<sub>2</sub>S and its role in <i>Mtb</i> physiology is lacking. We show that multidrug-resistant and drug-susceptible clinical <i>Mtb</i> strains produce H<sub>2</sub>S, whereas H<sub>2</sub>S production in non-pathogenic <i>M. smegmatis</i> is barely detectable. We identified Rv3684 (Cds1) as an H<sub>2</sub>S-producing enzyme in <i>Mtb</i> and show that <i>cds1</i> disruption reduces, but does not eliminate, H<sub>2</sub>S production, suggesting the involvement of multiple genes in H<sub>2</sub>S production. We identified endogenous H<sub>2</sub>S to be an effector molecule that maintains bioenergetic homeostasis by stimulating respiration primarily via cytochrome <i>bd</i>. Importantly, H<sub>2</sub>S 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, <i>Mtb</i>-generated H<sub>2</sub>S regulates redox homeostasis and susceptibility to anti-TB drugs clofazimine and rifampicin. These findings reveal previously unknown facets of <i>Mtb</i> physiology and have implications for routine laboratory culturing, understanding drug susceptibility, and improved diagnostics.https://www.mdpi.com/2076-3921/10/8/1285<i>Mycobacterium tuberculosis</i>H<sub>2</sub>Senergy metabolismbioenergeticsrespirationmetabolomics |
| spellingShingle | Tafara T. R. Kunota Md. Aejazur Rahman Barry E. Truebody Jared S. Mackenzie Vikram Saini Dirk A. Lamprecht John H. Adamson Ritesh R. Sevalkar Jack R. Lancaster Michael Berney Joel N. Glasgow Adrie J. C. Steyn <i>Mycobacterium tuberculosis</i> H<sub>2</sub>S Functions as a Sink to Modulate Central Metabolism, Bioenergetics, and Drug Susceptibility Antioxidants <i>Mycobacterium tuberculosis</i> H<sub>2</sub>S energy metabolism bioenergetics respiration metabolomics |
| title | <i>Mycobacterium tuberculosis</i> H<sub>2</sub>S Functions as a Sink to Modulate Central Metabolism, Bioenergetics, and Drug Susceptibility |
| title_full | <i>Mycobacterium tuberculosis</i> H<sub>2</sub>S Functions as a Sink to Modulate Central Metabolism, Bioenergetics, and Drug Susceptibility |
| title_fullStr | <i>Mycobacterium tuberculosis</i> H<sub>2</sub>S Functions as a Sink to Modulate Central Metabolism, Bioenergetics, and Drug Susceptibility |
| title_full_unstemmed | <i>Mycobacterium tuberculosis</i> H<sub>2</sub>S Functions as a Sink to Modulate Central Metabolism, Bioenergetics, and Drug Susceptibility |
| title_short | <i>Mycobacterium tuberculosis</i> H<sub>2</sub>S Functions as a Sink to Modulate Central Metabolism, Bioenergetics, and Drug Susceptibility |
| title_sort | i mycobacterium tuberculosis i h sub 2 sub s functions as a sink to modulate central metabolism bioenergetics and drug susceptibility |
| topic | <i>Mycobacterium tuberculosis</i> H<sub>2</sub>S energy metabolism bioenergetics respiration metabolomics |
| url | https://www.mdpi.com/2076-3921/10/8/1285 |
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