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 drugresistant 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.

Mitochondria: Powering the Innate Immune Response to Mycobacterium tuberculosis Infection

“…Most current tuberculosis treatment plans span between 6 and 9 months, providing ample opportunity for unintended side effects related to mitochondrial function. Rifampin, for example, has long been known to inhibit mitochondrial RNA polymerase and promote cytochrome c release (159). Pyrazinamide and isoniazid, two other first-line drugs, increase ROS production in ex vivo experiments (159).…”

“…Rifampin, for example, has long been known to inhibit mitochondrial RNA polymerase and promote cytochrome c release (159). Pyrazinamide and isoniazid, two other first-line drugs, increase ROS production in ex vivo experiments (159). If tuberculosis treatment alters mitochondrial function in a way that promotes Mtb pathogenesis, we may be inadvertently interfering with the ability of patients' own immune cells to control infection and/or inflammation.…”

The Iron Chelator Desferrioxamine Increases the Efficacy of Bedaquiline in Primary Human Macrophages Infected with BCG

“…The TTP values were noted for each sample and % change TTP values calculated. % change TTP was determined for each sample using the following Equation (1): BCG TTP Day5 − Sample TTP Day5 BCG TTP Day5 × 100 (1) where 'BCG TTP Day5 ' is the TTP of BCG-infected hMDMs alone and 'Sample TTP Day5 ' is the TTP of the sample of interest (such as BCG-infected hMDMs treated with a TB drug alone or a TB drug and DFX). All moxifloxacin and clofazimine drug titration experiments were undertaken prior to Biomerieux introduced their lyophilized antimicrobial supplement and nutrient supplement system; Biomerieux supplied their BacT bottles without nutrient supplementation, which had to be purchased separately and added to BacT bottles on the day of the experiment.…”

“…Antimicrobial therapy for patients with drug-sensitive and drug-resistant tuberculosis (TB) consists of a long, arduous, and complex treatment regimen for several months and in some cases years [ 1 ]. For over fifty years now, the mainstay for treating such patients with drug-resistant TB has been the administration of an array of antimicrobials [ 2 ].…”

“…For over fifty years now, the mainstay for treating such patients with drug-resistant TB has been the administration of an array of antimicrobials [ 2 ]. Unfortunately, long-term use of these antimicrobials has been well-characterised and is associated with numerous toxic side-effects [ 1 , 2 ]. Due to the protracted course of treatment, medication compliance is low, resulting in increased incidences of drug resistant strains.…”