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 t...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Company of Biologists
2020
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| _version_ | 1797096294830833664 |
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| author | Krishnamoorthy, G Kaiser, P Abed, UA Weiner, J Moura Alves, P Brinkmann, V Kaufmann, S |
| author_facet | Krishnamoorthy, G Kaiser, P Abed, UA Weiner, J Moura Alves, P Brinkmann, V Kaufmann, S |
| author_sort | Krishnamoorthy, G |
| collection | OXFORD |
| 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 in vivo was unconfirmed. Nevertheless, this proof-of-concept study encourages further investigations on the underlying mechanisms of LDHA inhibition and its significance in TB pathogenesis. |
| first_indexed | 2024-03-07T04:39:51Z |
| format | Journal article |
| id | oxford-uuid:d13baf86-0f20-4fab-bcb2-98deaf4c142f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:39:51Z |
| publishDate | 2020 |
| publisher | Company of Biologists |
| record_format | dspace |
| spelling | oxford-uuid:d13baf86-0f20-4fab-bcb2-98deaf4c142f2022-03-27T07:55:51ZFX11 limits Mycobacterium tuberculosis growth and potentiates bactericidal activity of isoniazid through host-directed activityJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d13baf86-0f20-4fab-bcb2-98deaf4c142fEnglishSymplectic ElementsCompany of Biologists2020Krishnamoorthy, GKaiser, PAbed, UAWeiner, JMoura Alves, PBrinkmann, VKaufmann, SLactate 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 in vivo was unconfirmed. Nevertheless, this proof-of-concept study encourages further investigations on the underlying mechanisms of LDHA inhibition and its significance in TB pathogenesis. |
| spellingShingle | Krishnamoorthy, G Kaiser, P Abed, UA Weiner, J Moura Alves, P Brinkmann, V Kaufmann, S FX11 limits Mycobacterium tuberculosis growth and potentiates bactericidal activity of isoniazid through host-directed activity |
| 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 |
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