Unique structural and mechanistic properties of mycobacterial F-ATP synthases: Implications for drug design

Kamariah, Neelagandan; Ragunathan, Priya; Shin, Joon; Saw, Wuan‐Geok; Wong, Chui Fann; Dick, Thomas; Grüber, Gerhard

doi:10.1016/j.pbiomolbio.2019.11.006

Cited by 25 publications

(17 citation statements)

References 56 publications

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“…A unique feature of Mtb ATP synthase is the suppression of the ATP hydrolase activity and its inability to establish a proton gradient. This could be an adaptive mechanism to prevent ATP waste under low oxygen conditions [ 89 , 90 ].…”

Section: Classification Of Drugs Targeting Energy-metabolism In mentioning

confidence: 99%

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

et al. 2020

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Tuberculosis remains the world’s top infectious killer: it caused a total of 1.5 million deaths and 10 million people fell ill with TB in 2018. Thanks to TB diagnosis and treatment, mortality has been falling in recent years, with an estimated 58 million saved lives between 2000 and 2018. However, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains is a major concern that might reverse this progress. Therefore, the development of new drugs acting upon novel mechanisms of action is a high priority in the global health agenda. With the approval of bedaquiline, which targets mycobacterial energy production, and delamanid, which targets cell wall synthesis and energy production, the energy-metabolism in Mtb has received much attention in the last decade as a potential target to investigate and develop new antimycobacterial drugs. In this review, we describe potent anti-mycobacterial agents targeting the energy-metabolism at different steps with a special focus on structure-activity relationship (SAR) studies of the most advanced compound classes.

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Section: Classification Of Drugs Targeting Energy-metabolism In mentioning

confidence: 99%

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

et al. 2020

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“…The mycobacterial F-ATP synthase (F 1 F O ATP synthase; Figure 1 ) contains the F 1 subunits α 3 :β 3 :γ:ε, the H + -translocating F O domain subunits a : c 9 , and the peripheral stalk subunits b : b’ : δ , which holds both domains together [ 10 , 11 ]. Proton conduction via the subunits a - c interface and ATP formation within the α 3 :β 3 hexamer are coupled by the rotary central stalk subunits γε [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting Mycobacterial F-ATP Synthase C-Terminal α Subunit Interaction Motif on Rotary Subunit γ

et al. 2021

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Mycobacteria regulate their energy (ATP) levels to sustain their survival even in stringent living conditions. Recent studies have shown that mycobacteria not only slow down their respiratory rate but also block ATP hydrolysis of the F-ATP synthase (α3:β3:γ:δ:ε:a:b:b’:c9) to maintain ATP homeostasis in situations not amenable for growth. The mycobacteria-specific α C-terminus (α533-545) has unraveled to be the major regulative of latent ATP hydrolysis. Its deletion stimulates ATPase activity while reducing ATP synthesis. In one of the six rotational states of F-ATP synthase, α533-545 has been visualized to dock deep into subunit γ, thereby blocking rotation of γ within the engine. The functional role(s) of this C-terminus in the other rotational states are not clarified yet and are being still pursued in structural studies. Based on the interaction pattern of the docked α533-545 region with subunit γ, we attempted to study the druggability of the α533-545 motif. In this direction, our computational work has led to the development of an eight-featured α533-545 peptide pharmacophore, followed by database screening, molecular docking, and pose selection, resulting in eleven hit molecules. ATP synthesis inhibition assays using recombinant ATP synthase as well as mycobacterial inverted membrane vesicles show that one of the hits, AlMF1, inhibited the mycobacterial F-ATP synthase in a micromolar range. The successful targeting of the α533-545-γ interaction motif demonstrates the potential to develop inhibitors targeting the α site to interrupt rotary coupling with ATP synthesis.

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“…The mycobacterial enzyme is composed of a membrane‐embedded F O complex (subunits a : b : b ′: c 9 ), which are responsible for H + ‐translocation from the periplasmic space to the cytoplasmic side, and the F 1 part (subunits α 3 :β 3 :γ:ϵ), which uses the proton‐motive force to synthesize ATP within the three catalytic αβ‐pairs (Figure A). This catalytic α 3 β 3 ‐headpiece is linked with the F O part via the two rotating central stalk subunits γ and ϵ, as well as the peripheral stalk subunits b , b ′ and δ …”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Mycobacterial F‐ATP Synthase Inhibitor and its Potency in Combination with Diarylquinolines

Hotra

Ragunathan

et al. 2020

Angewandte Chemie

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The F1FO‐ATP synthase is required for growth and viability of Mycobacterium tuberculosis and is a validated clinical target. A mycobacterium‐specific loop of the enzyme's rotary γ subunit plays a role in the coupling of ATP synthesis within the enzyme complex. We report the discovery of a novel antimycobacterial, termed GaMF1, that targets this γ subunit loop. Biochemical and NMR studies show that GaMF1 inhibits ATP synthase activity by binding to the loop. GaMF1 is bactericidal and is active against multidrug‐ as well as bedaquiline‐resistant strains. Chemistry efforts on the scaffold revealed a dynamic structure activity relationship and delivered analogues with nanomolar potencies. Combining GaMF1 with bedaquiline or novel diarylquinoline analogues showed potentiation without inducing genotoxicity or phenotypic changes in a human embryonic stem cell reporter assay. These results suggest that GaMF1 presents an attractive lead for the discovery of a novel class of anti‐tuberculosis F‐ATP synthase inhibitors.

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Unique structural and mechanistic properties of mycobacterial F-ATP synthases: Implications for drug design

Cited by 25 publications

References 56 publications

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

Targeting Mycobacterial F-ATP Synthase C-Terminal α Subunit Interaction Motif on Rotary Subunit γ

Discovery of a Novel Mycobacterial F‐ATP Synthase Inhibitor and its Potency in Combination with Diarylquinolines

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