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

Abstract

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.

Keywords: antimicrobials; bioenergetics; cellular metabolism; glycolysis; mitochondrial function; oxidative phosphorylation; tuberculosis.

Figure 1

An overview of the effect of tuberculosis antimicrobials on host mitochondrial function, bioenergetics and immune cell function. Tuberculosis (TB) antimicrobials, that are routinely used to fight TB infection, could affect a range of cellular processes, particularly mitochondrial function and various bioenergetic processes. These antimicrobials could alter MMP (isoniazid and ciprofloxacin), mitochondrial membrane permeability (rifampicin, ciprofloxacin and levofloxacin), mitochondrial mass (linezolid), or result in mitochondrial uncoupling (ciprofloxacin and levofloxacin). They could also inhibit electron transport chain complex activity (ciprofloxacin, levofloxacin, linezolid, bedaquiline, ethambutol, and rifampicin), ROS production (rifampicin and isoniazid), NO production (ciprofloxacin and levofloxacin), or ATP production (rifampicin, isoniazid and ciprofloxacin). Moreover, these antimicrobials have been shown to alter metabolic flux through OXPHOS (rifampicin, linezolid, bedaquiline, and clofazimine), glycolysis (bedaquiline, rifampicin, linezolid, moxifloxacin, ciprofloxacin, and clofazimine), while also affecting the production of TCA cycle intermediates (clofazimine). Such changes in mitochondrial function and host bioenergetics could also be linked with alterations in apoptosis (levofloxacin, ciprofloxacin, and linezolid), the autophagic process (isoniazid and bedaquiline) and a variety of inflammatory phenotypes (rifampicin, ciprofloxacin, levofloxacin, linezolid, bedaquiline, moxifloxacin, and clofazimine). Image produced with the aid of Servier Medical Art software (see copyright license at https://smart.servier.com).