Inhibition of host Lactate dehydrogenase A by a small-molecule limitsMycobacterium tuberculosisgrowth and potentiates bactericidal activity of isoniazid
Krishnamoorthy G., Kaiser P., Abed UA., Weiner J., Moura-Alves P., Brinkmann V., Kaufmann SHE.
<jats:title>ABSTRACT</jats:title><jats:p>Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate. Increased lactate turnover is shared by malignant and immune cells. Hypoxic lung granuloma in<jats:italic>Mycobacterium tuberculosis</jats:italic>-infected animals present elevated levels of<jats:italic>Ldha</jats:italic>and lactate. Such alteration in metabolic milieu could influence the outcome of interactions between<jats:italic>M. tuberculosis</jats:italic>and its infected immune cells. 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 host-directed therapeutic target. To this end, we administered FX11, a small-molecule NADH-competitive LDHA inhibitor, to<jats:italic>M. tuberculosis</jats:italic>infected C57BL/6J mice and Nos2<jats:sup>−/−</jats:sup>mice with hypoxic necrotizing lung TB lesions mimicking human pathology more closely. FX11 did not inhibit<jats:italic>M. tuberculosis</jats:italic>growth in aerobic/hypoxic liquid culture, but modestly reduced the pulmonary bacterial burden in C57BL/6J mice. Intriguingly, FX11 administration limited<jats:italic>M. tuberculosis</jats:italic>replication and onset of necrotic lesions in Nos2<jats:sup>−/−</jats:sup>mice. In this model, Isoniazid (INH) monotherapy has been known to exhibit biphasic killing kinetics owing to the probable selection of an INH-tolerant subpopulation. This adverse effect was corrected by adjunct FX11 treatment and augmented the INH-derived bactericidal effect against<jats:italic>M. tuberculosis</jats:italic>. Our findings therefore support LDHA as a potential target for host-directed adjunctive TB therapy and encourage further investigations into the underlying mechanism.</jats:p><jats:sec><jats:title>IMPORTANCE</jats:title><jats:p>Tuberculosis (TB) continues to be a global health threat of critical dimension. Standard TB drug treatment is prolonged and cumbersome. Inappropriate treatment or non-compliance results in emergence of drug-resistant<jats:italic>Mycobacterium tuberculosis</jats:italic>strains (MDR-TB) that render current treatment options ineffective. Targeting the host immune system as adjunct therapy to augment bacterial clearance is attractive as it is also expected to be effective against MDR-TB. Here, we provide evidence that pharmaceutical blockade of host lactate dehydrogenase A (LDHA) by a small-molecule limits<jats:italic>M. tuberculosis</jats:italic>growth and reduces pathology. Notably, LDHA inhibition potentiates the effect of Isoniazid, a first-line anti-TB drug. Hence, its implications of our findings for short-term TB treatment are profound. In sum, our findings establish murine LDHA as a potential target for host-directed TB therapy.</jats:p></jats:sec>