Bioenergetic Inhibitors: Antibiotic Efficacy and Mechanisms of Action in Mycobacterium tuberculosis

Abstract

Development of novel anti-tuberculosis combination regimens that increase efficacy and reduce treatment timelines will improve patient compliance, limit side-effects, reduce costs, and enhance cure rates. Such advancements would significantly improve the global TB burden and reduce drug resistance acquisition. Bioenergetics has received considerable attention in recent years as a fertile area for anti-tuberculosis drug discovery. Targeting the electron transport chain (ETC) and oxidative phosphorylation machinery promises not only to kill growing cells but also metabolically dormant bacilli that are inherently more drug tolerant. Over the last two decades, a broad array of drugs targeting various ETC components have been developed. Here, we provide a focused review of the current state of art of bioenergetic inhibitors of Mtb with an in-depth analysis of the metabolic and bioenergetic disruptions caused by specific target inhibition as well as their synergistic and antagonistic interactions with other drugs. This foundation is then used to explore the reigning theories on the mechanisms of antibiotic-induced cell death and we discuss how bioenergetic inhibitors in particular fail to be adequately described by these models. These discussions lead us to develop a clear roadmap for new lines of investigation to better understand the mechanisms of action of these drugs with complex mechanisms as well as how to leverage that knowledge for the development of novel, rationally-designed combination therapies to cure TB.

Keywords: Mycobacterium tuberculosis; Q203; bactericidal; bedaquiline; bioenergetics; electron transport chain; persistence.

Figure 1

The electron transport chain of Mycobacterium tuberculosis and compounds targeting each component. Clofazimine (CFZ), Phenothiazines (PTZ), 3-nitropropionate (3-NP), Lansoprazole (LPZ), Bedaquiline (BDQ), Pyrazinamide (PZA).

Figure 2

Mechanisms of conventional, bactericidal antibiotic-induced cell death. Conventional, bactericidal drugs have multiple components of their mechanisms of action which lead to cell death, beginning with specific target inhibition, which leads to damaged biomolecules, as well as altered metabolism and ROS production.

Figure 3

Mechanism of futile cycling induced by defective synthesis from bactericidal antibiotic challenge. (A) Under standard growth conditions, biosynthetic substrates (nucleic acids, amino acids, peptidoglycans) are synthesized into biomolecules (DNA/RNA, proteins, cell wall). (B) Conventional bactericidal compounds induce defective synthesis (e.g. mistranslation by aminoglycosides), which is proposed to generate an ATP-consuming futile cycle, as well as direct deleterious effects caused by incorporation of some of the defective biomolecules into cellular structures and machinery. (C) Bacteriostatic compounds appear to inhibit both standard biosynthesis and defective biosynthesis, disrupting the futile cycle induced by bactericidal compounds.