Targeting the ATP synthase in bacterial and fungal pathogens: beyond Mycobacterium tuberculosis
ABSTRACT: The ATP synthase is a multicomponent enzyme that is largely conserved across the kingdoms of life. In many species the ATP synthase is central in the synthesis of ATP by using the electrochemical proton gradient generated via the electron transport chain. Bacteria inhabit very diverse ecol...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | Journal of Global Antimicrobial Resistance |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213716522000303 |
| _version_ | 1828810488761286656 |
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| author | Martin Vestergaard Dirk Bald Hanne Ingmer |
| author_facet | Martin Vestergaard Dirk Bald Hanne Ingmer |
| author_sort | Martin Vestergaard |
| collection | DOAJ |
| description | ABSTRACT: The ATP synthase is a multicomponent enzyme that is largely conserved across the kingdoms of life. In many species the ATP synthase is central in the synthesis of ATP by using the electrochemical proton gradient generated via the electron transport chain. Bacteria inhabit very diverse ecological niches; hence their metabolism to extract nutrients and generation of ATP varies from species to species. Some species are obligate aerobes (e.g., Mycobacterium tuberculosis), relying on oxidative phosphorylation for ATP synthesis, whereas others are strict anaerobes (e.g., Clostridioides difficile) relying primarily on substrate-level phosphorylation using various fermentative pathways. Yet other species, such as Staphylococcus aureus and Escherichia coli are facultative anaerobes and can convert energy via both respiratory and fermentative pathways. The metabolic propensity and growth conditions experienced by bacterial species have a great impact on the necessity of a functional ATP synthase for viability.The ATP synthase has been validated as a druggable target with the approval of the ATP synthase inhibitor bedaquiline for treatment of M. tuberculosis, an organism in which the ATP synthase is essential for growth. Currently, no ATP synthase inhibitors are in clinical use against non-mycobacterial pathogens.In this review, the physiological functions of the ATP synthase in various bacterial pathogens are discussed in relation to the metabolic pathways utilized for providing energy. The ATP synthase is essential in important pathogenic species that are obligate aerobes, obligate anaerobes and aerotolerant anaerobes, whereas it is dispensable for growth in most facultative anaerobic pathogens. Interference with the ATP synthase in facultative anaerobes has physiological consequences, such as membrane hyperpolarization, which can be exploited for combination therapies.Collectively, the available data indicate that the ATP synthase is an interesting target for development of new antimicrobials beyond M. tuberculosis. |
| first_indexed | 2024-12-12T09:12:39Z |
| format | Article |
| id | doaj.art-7a0c9cc51a714ba9817513dcd9af94ae |
| institution | Directory Open Access Journal |
| issn | 2213-7165 |
| language | English |
| last_indexed | 2024-12-12T09:12:39Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Global Antimicrobial Resistance |
| spelling | doaj.art-7a0c9cc51a714ba9817513dcd9af94ae2022-12-22T00:29:28ZengElsevierJournal of Global Antimicrobial Resistance2213-71652022-06-01292941Targeting the ATP synthase in bacterial and fungal pathogens: beyond Mycobacterium tuberculosisMartin Vestergaard0Dirk Bald1Hanne Ingmer2Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, DenmarkDepartment of Molecular Cell Biology, AIMMS, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark; Corresponding author. Mailing address: Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Stigbøjlen 4, DK-1870 Frederiksberg C, Denmark.ABSTRACT: The ATP synthase is a multicomponent enzyme that is largely conserved across the kingdoms of life. In many species the ATP synthase is central in the synthesis of ATP by using the electrochemical proton gradient generated via the electron transport chain. Bacteria inhabit very diverse ecological niches; hence their metabolism to extract nutrients and generation of ATP varies from species to species. Some species are obligate aerobes (e.g., Mycobacterium tuberculosis), relying on oxidative phosphorylation for ATP synthesis, whereas others are strict anaerobes (e.g., Clostridioides difficile) relying primarily on substrate-level phosphorylation using various fermentative pathways. Yet other species, such as Staphylococcus aureus and Escherichia coli are facultative anaerobes and can convert energy via both respiratory and fermentative pathways. The metabolic propensity and growth conditions experienced by bacterial species have a great impact on the necessity of a functional ATP synthase for viability.The ATP synthase has been validated as a druggable target with the approval of the ATP synthase inhibitor bedaquiline for treatment of M. tuberculosis, an organism in which the ATP synthase is essential for growth. Currently, no ATP synthase inhibitors are in clinical use against non-mycobacterial pathogens.In this review, the physiological functions of the ATP synthase in various bacterial pathogens are discussed in relation to the metabolic pathways utilized for providing energy. The ATP synthase is essential in important pathogenic species that are obligate aerobes, obligate anaerobes and aerotolerant anaerobes, whereas it is dispensable for growth in most facultative anaerobic pathogens. Interference with the ATP synthase in facultative anaerobes has physiological consequences, such as membrane hyperpolarization, which can be exploited for combination therapies.Collectively, the available data indicate that the ATP synthase is an interesting target for development of new antimicrobials beyond M. tuberculosis.http://www.sciencedirect.com/science/article/pii/S2213716522000303ATP synthaseMetabolismInhibitorsMembrane polarizationAntibiotic adjuvant target |
| spellingShingle | Martin Vestergaard Dirk Bald Hanne Ingmer Targeting the ATP synthase in bacterial and fungal pathogens: beyond Mycobacterium tuberculosis Journal of Global Antimicrobial Resistance ATP synthase Metabolism Inhibitors Membrane polarization Antibiotic adjuvant target |
| title | Targeting the ATP synthase in bacterial and fungal pathogens: beyond Mycobacterium tuberculosis |
| title_full | Targeting the ATP synthase in bacterial and fungal pathogens: beyond Mycobacterium tuberculosis |
| title_fullStr | Targeting the ATP synthase in bacterial and fungal pathogens: beyond Mycobacterium tuberculosis |
| title_full_unstemmed | Targeting the ATP synthase in bacterial and fungal pathogens: beyond Mycobacterium tuberculosis |
| title_short | Targeting the ATP synthase in bacterial and fungal pathogens: beyond Mycobacterium tuberculosis |
| title_sort | targeting the atp synthase in bacterial and fungal pathogens beyond mycobacterium tuberculosis |
| topic | ATP synthase Metabolism Inhibitors Membrane polarization Antibiotic adjuvant target |
| url | http://www.sciencedirect.com/science/article/pii/S2213716522000303 |
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