Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis

Saw, Wuan‐Geok; Wu, Mu-Lu; Ragunathan, Priya; Biuković, Goran; Lau, Aik-Meng; Shin, Joon; Harikishore, Amaravadhi; Cheung, Chen‐Yi; Hards, Kiel; Sarathy, Jickky Palmae; Bates, Roderick W.; Cook, Gregory M.; Dick, Thomas; Grüber, Gerhard

doi:10.1038/s41598-019-53107-3

Cited by 31 publications

(41 citation statements)

References 45 publications

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“…The growing interest in ATP synthase as a target and the emerging of BDQ resistance has resulted in a number of HTS and in silico screenings to identify additional options for ATP synthase inhibition and novel chemical entities for medicinal chemistry optimization, such as epigallocatechin [ 114 ], thiazolidones [ 115 ], and diaminoquinazolines [ 116 ].…”

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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“…Recently, the solution Nuclear Magnetic Resonance (NMR) structure of the Mtb ε-subunit was resolved [56]. This structure, together with genetic and biochemical studies, showed that the Mtb ε-subunit plays a novel role in ATP synthesis by linking c-ring rotation to ATP synthesis at the α 3 β 3 -headpiece [56][57][58]. Critical to this function is the Mtb ε-subunit's inter-domain amino acid interaction network, which transmits information on c-ring rotation throughout the subunit and to its C-terminus.…”

Section: Disrupting the Mycobacterial F-atp Synthase ε-Subunit's Funcmentioning

confidence: 99%

“…The C-terminus can adopt an extended conformation to interact with the α 3 β 3 -headpiece to pass on this information. This process is proposed to contribute to the initiation of ATP synthesis at the α 3 β 3 -headpiece [56,58]. Through NMR titration, BDQ's binding site on the Mtb ε-subunit was uncovered to be the A10-W16 amino acid region [56].…”

Section: Disrupting the Mycobacterial F-atp Synthase ε-Subunit's Funcmentioning

confidence: 99%

Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline

2019

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Bedaquiline (BDQ) inhibits ATP generation in Mycobacterium tuberculosis by interfering with the F-ATP synthase activity. Two mechanisms of action of BDQ are broadly accepted. A direct mechanism involves BDQ binding to the enzyme's c-ring to block its rotation, thus inhibiting ATP synthesis in the enzyme's catalytic α 3 β 3 -headpiece. An indirect mechanism involves BDQ uncoupling electron transport in the electron transport chain from ATP synthesis at the F-ATP synthase. In a recently uncovered second direct mechanism, BDQ binds to the enzyme's ε-subunit to disrupt its ability to link c-ring rotation to ATP synthesis at the α 3 β 3 -headpiece. However, this mechanism is controversial as the drug's binding affinity for the isolated ε-subunit protein is moderate and spontaneous resistance mutants in the ε-subunit cannot be isolated. Recently, the new, structurally distinct BDQ analogue TBAJ-876 was utilized as a chemical probe to revisit BDQ's mechanisms of action. In this review, we first summarize discoveries on BDQ's mechanisms of action and then describe the new insights derived from the studies of TBAJ-876. The TBAJ-876 investigations confirm the c-ring as a target, while also supporting a functional role for targeting the ε-subunit. Surprisingly, the new findings suggest that the uncoupler mechanism does not play a key role in BDQ's anti-mycobacterial activity.Concentration (MIC) of 0.002-0.013 µg/mL [10,11]). This potent activity holds true in vivo where BDQ has demonstrated accelerated sterilizing activity [12], with four months of BDQ treatment being as efficacious as six months of first-line drug treatment of Mtb-infected mice [13]. Importantly, BDQ also displays bactericidal activity against non-replicating Mtb at therapeutically attainable concentrations [14,15]. In the clinical setting, the usage of BDQ has produced promising results. Studies have shown that the usage of the drug for drug-resistant TB treatment improved sputum conversion and reduced chemotherapy duration and relapse [16][17][18][19]. Hence, new BDQ-containing drug regimens are currently being explored in Phase III clinical trials, such as the STREAM and SimpliciTB trials [20]. One such trial, the Nix-TB trial, resulted in the recent US FDA approval of the BDQ-pretomanid-linezolid six months, all-oral regimen for the treatment of drug-resistant TB [21,22].

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“…The removal of its C-terminal resulted in an increased ATP hydrolysis rate and decreased ATP synthesis [86]. Furthermore, Saw et al, demonstrated that this site is amenable to chemical inhibition in M. smeg by epigallocatechin gallate, the most abundant catechin in green tea [87]. Other subunits involved in the regulation of ATP hydrolysis include the γand αsubunits of the F1 module [88,89].…”

Section: Atp Synthasementioning

confidence: 99%

Oxidative Phosphorylation—an Update on a New, Essential Target Space for Drug Discovery in Mycobacterium tuberculosis

2020

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New drugs with new mechanisms of action are urgently required to tackle the global tuberculosis epidemic. Following the FDA-approval of the ATP synthase inhibitor bedaquiline (Sirturo®), energy metabolism has become the subject of intense focus as a novel pathway to exploit for tuberculosis drug development. This enthusiasm stems from the fact that oxidative phosphorylation (OxPhos) and the maintenance of the transmembrane electrochemical gradient are essential for the viability of replicating and non-replicating Mycobacterium tuberculosis (M. tb), the etiological agent of human tuberculosis (TB). Therefore, new drugs targeting this pathway have the potential to shorten TB treatment, which is one of the major goals of TB drug discovery. This review summarises the latest and key findings regarding the OxPhos pathway in M. tb and provides an overview of the inhibitors targeting various components. We also discuss the potential of new regimens containing these inhibitors, the flexibility of this pathway and, consequently, the complexity in targeting it. Lastly, we discuss opportunities and future directions of this drug target space.

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Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis

Cited by 31 publications

References 45 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

Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline

Oxidative Phosphorylation—an Update on a New, Essential Target Space for Drug Discovery in Mycobacterium tuberculosis

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