Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery

Abstract

Mycobacterium tuberculosis (Mtb) exhibits remarkable metabolic flexibility that enables it to survive a plethora of host environments during its life cycle. With the advent of bedaquiline for treatment of multidrug-resistant tuberculosis, oxidative phosphorylation has been validated as an important target and a vulnerable component of mycobacterial metabolism. Exploiting the dependence of Mtb on oxidative phosphorylation for energy production, several components of this pathway have been targeted for the development of new antimycobacterial agents. This includes targeting NADH dehydrogenase by phenothiazine derivatives, menaquinone biosynthesis by DG70 and other compounds, terminal oxidase by imidazopyridine amides and ATP synthase by diarylquinolines. Importantly, oxidative phosphorylation also plays a critical role in the survival of persisters. Thus, inhibitors of oxidative phosphorylation can synergize with frontline TB drugs to shorten the course of treatment. In this review, we discuss the oxidative phosphorylation pathway and development of its inhibitors in detail.

Keywords: Mycobacterium tuberculosis; Q203; SQ109; antimycobacterials; bedaquiline; bioenergetics; drugs; electron transport chain; oxidative phosphorylation.

Figure 1

Mycobacterial menaquinone biosynthesis pathway and its inhibitors. (A–H) represent chorismate, isochorismate, 2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate, o-succinylbenzoate, o-succinylbenzoyl-CoA, 1,4-dihydroxy-2-naphthoyl CoA, demethylmenaquinone, and menaquinone respectively. Drugs that target the menaquinone biosynthesis enzymes are shown by red flathead arrows.

Figure 2

Inhibition of cytochrome bc₁ by LPZ and Q203. The sulfoxide reduction of LPZ converts it to active LPZS, which can bind QcrB of cytochrome bc₁ complex. Q203, an imidazopyridine amide, also targets the QcrB subunit of cytochrome bc₁ complex. Inhibition of QcrB forces the mycobacteria to use energetically less efficient cytochrome bd oxidase, a decrease in proton motive force (PMF) and ATP levels. Red flathead arrows indicate binding with subunit and inhibition of cytochrome bc₁ complex.

Figure 3

Schematic view of ATP synthase and its interaction with bedaquiline (BDQ). (A) Depicts the top view of C-ring of ATP synthase F_o complex and comparison of C-rings of mitochondria (C₁₀), E. coli (C₈) and mycobacteria (C₉). (B) BDQ binds between the two c subunits of the C-ring. The interaction of BDQ with C ring is illustrated in the zoomed region. BDQ specifically interacts with Glu⁶⁵ (E65), Phe⁶⁹ (F69), Leu⁶³ (L63), Asp³² (D32), and Ile⁷⁰ (I70) of adjacent c subunits.

Figure 4

Schematic representation of the mycobacterial electron transport chain and its inhibitors. NADH derived via glycolysis and tricarboxylic acid (TCA) cycle feds electrons into the electron transport chain by NADH dehydrogenase. The menaquinone (MK) pool can be reduced by primary dehydrogenases such as NADH dehydrogenases (NDH1 and NDH2) and via succinate dehydrogenase (SDH). Electrons from the menaquinone pool are accepted directly by cytochrome bd-type terminal oxidase or via bc₁-aa₃ supercomplex. A proton motive force (PMF) is generated during electron transport chain because of pumping of protons across the membrane. This PMF is used by the ATP synthase to generate ATP. Drugs that target the oxidative phosphorylation are shown by red flathead arrows. Abbreviations: CFZ, clofazimine; TPZ, trifluoperazine; QPs, quinolinyl pyrimidines; Q203, imidazopyridine amide; LPZ, lansoprazole; Ro 48-8071, (4-bromophenyl)[2-fluoro-4-[[6-(methyl-2-propenylamino)hexyl]oxy]phenyl]-methanone; DG70,biphenyl amide; BDQ, bedaquiline; SQR, squaramide; SQ109, N-adamantan-2-yl-N-((E)-3,7-dimethyl-octa-2,6-dienyl)-ethane-1,2-diamine; PYZ, pyrazinamide. Red arrows in the TCA cycle depict the glyoxylate shunt.