FX11 limits Mycobacterium tuberculosis growth and potentiates bactericidal activity of isoniazid through host-directed activity

• Published in: Disease models & mechanisms Vol. 13; no. 3
• Main Authors: Krishnamoorthy, Gopinath, Kaiser, Peggy, Abu Abed, Ulrike, Weiner, January, Moura-Alves, Pedro, Brinkmann, Volker, Kaufmann, Stefan H. E.
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 30.03.2020; The Company of Biologists
• Subjects: Aerosols; Animals; Bone marrow; Disease Models, Animal; Drug dosages; Drug resistance; Experiments; Female; fx11; Glycerol; glycolysis; granuloma; Granulomas; host-directed therapy; Host-Pathogen Interactions - drug effects; Hypoxia; immunometabolism; Infections; Isoniazid - pharmacology; lactate dehydrogenase a; Metabolism; Metabolites; Mice, Inbred C57BL; mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - growth & development; Mycobacterium tuberculosis - metabolism; Naphthalenes - pharmacology; Pathogens; Tuberculosis; Granuloma; Immunometabolism; FX11; Mycobacterium tuberculosis; Lactate dehydrogenase A; Glycolysis; Hypoxia; Host-directed therapy
• ISSN: 1754-8403; 1754-8411; 1754-8411
• DOI: 10.1242/dmm.041954

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.