FX11 limits Mycobacterium tuberculosis growth and potentiates bactericidal activity of isoniazid through host-directed activity
Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate, and increased lactate turnover is exhibited by malignant and infected immune cells. Hypoxic lung granuloma in Mycobacterium tuberculosis-infected animals present elevated levels of Ldha and lactate. Such alterations in...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2020-03-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/13/3/dmm041954 |
| _version_ | 1818519925604483072 |
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| author | Gopinath Krishnamoorthy Peggy Kaiser Ulrike Abu Abed January Weiner Pedro Moura-Alves Volker Brinkmann Stefan H. E. Kaufmann |
| author_facet | Gopinath Krishnamoorthy Peggy Kaiser Ulrike Abu Abed January Weiner Pedro Moura-Alves Volker Brinkmann Stefan H. E. Kaufmann |
| author_sort | Gopinath Krishnamoorthy |
| collection | DOAJ |
| description | Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate, and increased lactate turnover is exhibited by malignant and infected immune cells. Hypoxic lung granuloma in Mycobacterium tuberculosis-infected animals present elevated levels of Ldha and lactate. Such alterations in the metabolic milieu could influence the outcome of host-M. tuberculosis interactions. Given the central role of LDHA for tumorigenicity, targeting lactate metabolism is a promising approach for cancer therapy. Here, we sought to determine the importance of LDHA for tuberculosis (TB) disease progression and its potential as a target for host-directed therapy. To this end, we orally administered FX11, a known small-molecule NADH-competitive LDHA inhibitor, to M. tuberculosis-infected C57BL/6J mice and Nos2−/− mice with hypoxic necrotizing lung TB lesions. FX11 did not inhibit M. tuberculosis growth in aerobic/hypoxic liquid culture, but modestly reduced the pulmonary bacterial burden in C57BL/6J mice. Intriguingly, FX11 administration limited M. tuberculosis replication and onset of necrotic lung lesions in Nos2−/− mice. In this model, isoniazid (INH) monotherapy has been known to exhibit biphasic killing kinetics owing to the probable selection of an INH-tolerant bacterial subpopulation. However, adjunct FX11 treatment corrected this adverse effect and resulted in sustained bactericidal activity of INH against M. tuberculosis. As a limitation, LDHA inhibition as an underlying cause of FX11-mediated effect could not be established as the on-target effect of FX11 in vivo was unconfirmed. Nevertheless, this proof-of-concept study encourages further investigation on the underlying mechanisms of LDHA inhibition and its significance in TB pathogenesis. |
| first_indexed | 2024-12-11T01:30:34Z |
| format | Article |
| id | doaj.art-1d4e6545a6c14d64b47bf69114bc310d |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-11T01:30:34Z |
| publishDate | 2020-03-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-1d4e6545a6c14d64b47bf69114bc310d2022-12-22T01:25:23ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112020-03-0113310.1242/dmm.041954041954FX11 limits Mycobacterium tuberculosis growth and potentiates bactericidal activity of isoniazid through host-directed activityGopinath Krishnamoorthy0Peggy Kaiser1Ulrike Abu Abed2January Weiner3Pedro Moura-Alves4Volker Brinkmann5Stefan H. E. Kaufmann6 Department of Immunology, Max Planck Institute for Infection Biology, Berlin 10117, Germany Department of Immunology, Max Planck Institute for Infection Biology, Berlin 10117, Germany Core Facility Microscopy, Max Planck Institute for Infection Biology, Berlin 10117, Germany Department of Immunology, Max Planck Institute for Infection Biology, Berlin 10117, Germany Department of Immunology, Max Planck Institute for Infection Biology, Berlin 10117, Germany Core Facility Microscopy, Max Planck Institute for Infection Biology, Berlin 10117, Germany Department of Immunology, Max Planck Institute for Infection Biology, Berlin 10117, Germany Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate, and increased lactate turnover is exhibited by malignant and infected immune cells. Hypoxic lung granuloma in Mycobacterium tuberculosis-infected animals present elevated levels of Ldha and lactate. Such alterations in the metabolic milieu could influence the outcome of host-M. tuberculosis interactions. Given the central role of LDHA for tumorigenicity, targeting lactate metabolism is a promising approach for cancer therapy. Here, we sought to determine the importance of LDHA for tuberculosis (TB) disease progression and its potential as a target for host-directed therapy. To this end, we orally administered FX11, a known small-molecule NADH-competitive LDHA inhibitor, to M. tuberculosis-infected C57BL/6J mice and Nos2−/− mice with hypoxic necrotizing lung TB lesions. FX11 did not inhibit M. tuberculosis growth in aerobic/hypoxic liquid culture, but modestly reduced the pulmonary bacterial burden in C57BL/6J mice. Intriguingly, FX11 administration limited M. tuberculosis replication and onset of necrotic lung lesions in Nos2−/− mice. In this model, isoniazid (INH) monotherapy has been known to exhibit biphasic killing kinetics owing to the probable selection of an INH-tolerant bacterial subpopulation. However, adjunct FX11 treatment corrected this adverse effect and resulted in sustained bactericidal activity of INH against M. tuberculosis. As a limitation, LDHA inhibition as an underlying cause of FX11-mediated effect could not be established as the on-target effect of FX11 in vivo was unconfirmed. Nevertheless, this proof-of-concept study encourages further investigation on the underlying mechanisms of LDHA inhibition and its significance in TB pathogenesis.http://dmm.biologists.org/content/13/3/dmm041954glycolysislactate dehydrogenase afx11mycobacterium tuberculosisgranulomahypoxiaimmunometabolismhost-directed therapy |
| spellingShingle | Gopinath Krishnamoorthy Peggy Kaiser Ulrike Abu Abed January Weiner Pedro Moura-Alves Volker Brinkmann Stefan H. E. Kaufmann FX11 limits Mycobacterium tuberculosis growth and potentiates bactericidal activity of isoniazid through host-directed activity Disease Models & Mechanisms glycolysis lactate dehydrogenase a fx11 mycobacterium tuberculosis granuloma hypoxia immunometabolism host-directed therapy |
| title | FX11 limits Mycobacterium tuberculosis growth and potentiates bactericidal activity of isoniazid through host-directed activity |
| title_full | FX11 limits Mycobacterium tuberculosis growth and potentiates bactericidal activity of isoniazid through host-directed activity |
| title_fullStr | FX11 limits Mycobacterium tuberculosis growth and potentiates bactericidal activity of isoniazid through host-directed activity |
| title_full_unstemmed | FX11 limits Mycobacterium tuberculosis growth and potentiates bactericidal activity of isoniazid through host-directed activity |
| title_short | FX11 limits Mycobacterium tuberculosis growth and potentiates bactericidal activity of isoniazid through host-directed activity |
| title_sort | fx11 limits mycobacterium tuberculosis growth and potentiates bactericidal activity of isoniazid through host directed activity |
| topic | glycolysis lactate dehydrogenase a fx11 mycobacterium tuberculosis granuloma hypoxia immunometabolism host-directed therapy |
| url | http://dmm.biologists.org/content/13/3/dmm041954 |
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