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

Gopinath Krishnamoorthy,January Weiner,Volker Brinkmann,Stefan H E Kaufmann,Peggy Kaiser,Pedro Moura-Alves,Ulrike Abu Abed

doi:10.1242/dmm.041954

Abstract

ABSTRACTLactate 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.

Highlights

We assessed the FX11-induced effect in interferon-gamma (IFN-γ)-stimulated, but uninfected, murine bone marrow-derived macrophages (BMDMs)
Our observations are intriguing and consistent with those reported in other studies, wherein the pharmacological inhibition of host immune function has been shown to potentiate the efficacy of antiTB drugs and has been implicated as an adjunct host-directed therapy with the potential to improve treatment outcome (Cheng et al, 2017; Costa et al, 2016; Dutta et al, 2007; Gupta et al, 2017; Maiga et al, 2015; Singhal et al, 2014; Subbian et al, 2016, 2011; Xu et al, 2018)
Our results were inconclusive in confirming the on-target effect and it is not clear whether Lactate dehydrogenase A (LDHA) inhibition is an underlying cause of FX11mediated effect

Summary

Introduction

Radiotracer imaging has revealed heterogeneity – in size, metabolism and infection – within and between granulomas in a single host infected with Mycobacterium tuberculosis (Lenaerts et al, 2015; Lin et al, 2014). The impact of metabolic pathways (such as glycolysis) and mitochondrial respiration on immune functions and host-pathogen interactions is increasingly accepted (Eisenreich et al, 2017; Escoll and Buchrieser, 2018; Escoll et al, 2017; Kiran et al, 2016; Olive and Sassetti, 2016; Russell et al, 2019). Understanding of pathogen-induced immunometabolic dysregulation in granuloma can provide insights into the vital pathways in the infected host and thereby reveal novel therapeutic target candidates

Methods

Results

Conclusion