Understanding and Exploiting the Effect of Tuberculosis Antimicrobials on Host Mitochondrial Function and Bioenergetics.

Almost 140 years after its discovery, tuberculosis remains the leading infectious cause of death globally. For half a century, patients with drug-sensitive and drug-resistant tuberculosis have undergone long, arduous, and complex treatment processes with several antimicrobials that primarily function through direct bactericidal activity. Long-term utilization of these antimicrobials has been well-characterized and associated with numerous toxic side-effects. With the prevalence of drug-resistant strains on the rise and new therapies for tuberculosis urgently required, a more thorough understanding of these antimicrobials is a necessity. In order to progress from the "one size fits all" treatment approach, understanding how these antimicrobials affect mitochondrial function and bioenergetics may provide further insight into how these drugs affect the overall functions of host immune cells during tuberculosis infection. Such insights may help to inform future studies, instigate discussion, and help toward establishing personalized approaches to using such antimicrobials which could help to pave the way for more tailored treatment regimens. While recent research has highlighted the important role mitochondria and bioenergetics play in infected host cells, only a small number of studies have examined how these antimicrobials affect mitochondrial function and immunometabolic processes within these immune cells. This short review highlights how these antimicrobials affect key elements of mitochondrial function, leading to further discussion on how they affect bioenergetic processes, such as glycolysis and oxidative phosphorylation, and how antimicrobial-induced alterations in these processes can be linked to downstream changes in inflammation, autophagy, and altered bactericidal activity.

Desferrioxamine Supports Metabolic Function in Primary Human Macrophages Infected With Mycobacterium tuberculosis.

Tuberculosis is the single biggest infectious killer in the world and presents a major global health challenge. Antimicrobial therapy requires many months of multiple drugs and incidences of drug resistant tuberculosis continues to rise. Consequently, research is now focused on the development of therapies to support the function of infected immune cells. HIF1α-mediated induction of aerobic glycolysis is integral to the host macrophage response during infection with Mtb, as this promotes bacillary clearance. Some iron chelators have been shown to modulate cellular metabolism through the regulation of HIF1α. We examined if the iron chelator, desferrioxamine (DFX), could support the function of primary human macrophages infected with Mtb. Using RT-PCR, we found that DFX promoted the expression of key glycolytic enzymes in Mtb-infected primary human MDMs and human alveolar macrophages. Using Seahorse technology, we demonstrate that DFX enhances glycolytic metabolism in Mtb-stimulated human MDMs, while helping to enhance glycolysis during mitochondrial distress. Furthermore, the effect of DFX on glycolysis was not limited to Mtb infection as DFX also boosted glycolytic metabolism in uninfected and LPS-stimulated cells. DFX also supports innate immune function by inducing IL1ß production in human macrophages during early infection with Mtb and upon stimulation with LPS. Moreover, using hypoxia, Western blot and ChIP-qPCR analyses, we show that DFX modulates IL1ß levels in these cells in a HIF1α-mediated manner. Collectively, our data suggests that DFX exhibits potential to enhance immunometabolic responses and augment host immune function during early Mtb infection, in selected clinical settings.