Novel, potent, orally bioavailable and selective mycobacterial ATP synthase inhibitors that demonstrated activity against both replicating and non-replicating M. tuberculosis

Singh, Supriya; Roy, Kuldeep K.; Khan, Shaheb Raj; Kashyap, Vivek K.; Sharma, Abhisheak; Jaiswal, Swati; Sharma, Sandeep; Krishnan, Manju Y.; Chaturvedi, Vineeta; Lal, Jawahar; Sinha, Sudhir; Dasgupta, Arunava; Srivastava, Rohit; Saxena, Anil Kumar

doi:10.1016/j.bmc.2014.12.060

Cited by 53 publications

(19 citation statements)

References 22 publications

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“…The respiratory chain enzyme complexes of mycobacteria, generating a proton motive force (PMF) across the bacterial cytoplasmatic membrane, as well as the F‐ATP synthase, which utilizes this force for ATP synthesis, have been identified as potential drug targets for treatment of tuberculosis, which is mainly caused by the bacterium Mycobacterium tuberculosis . Mycobacterial F‐ATP synthase has been shown to be a target of bedaquiline (BDQ), which selectively inhibits this enzyme in a variety of mycobacterial strains .…”

Section: Introductionmentioning

confidence: 99%

“…The respiratory chain enzyme complexes of mycobacteria, generating a proton motive force (PMF) across the bacterial cytoplasmatic membrane, as well as the F-ATP synthase, which utilizes this force for ATP synthesis, have been identified as potential drug targets for treatment of tuberculosis, which is mainly caused by the bacterium Mycobacterium tuberculosis [1][2][3][4]. Mycobacterial F-ATP synthase has been shown to be Abbreviations ACMA, 9-amino-6-chloro-2-methoxyacridine; BDQ, bedaquiline; IMV, inverted membrane vesicle; NBD-Cl, 4-chloro-7-nitrobenzofurazan; NDH-2, type II NADH dehydrogenase; SF6847, 3, 5-di tert-butyl-4-hydroxybenzylidenemalononitrile.…”

Section: Introductionmentioning

confidence: 99%

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Deletion of a unique loop in the mycobacterial F‐ATP synthase γ subunit sheds light on its inhibitory role in ATP hydrolysis‐driven H⁺ pumping

et al. 2016

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O -ATP synthase is one of the enzymes that is essential to meet the energy requirement of both the proliferating aerobic and hypoxic dormant stages of the life cycle of mycobacteria. Most F-ATP synthases consume ATP in the a 3 :b 3 headpiece to drive the c subunit, which couples ATP cleavage with proton pumping in the c ring of F O via the bottom of the c subunit. ATPase-driven H + pumping is latent in mycobacteria. The presence of a unique 14 amino acid residue loop of the mycobacterial c subunit has been described and aligned in close vicinity to the c-ring loop Priya R et al. (2013) J Bioenerg Biomembr 45, 121-129 Here, we used inverted membrane vesicles (IMVs) of fast-growing Mycobacterium smegmatis and a variety of covalent and non-covalent inhibitors to characterize the ATP hydrolysis activity of the F-ATP synthase inside IMVs. These vesicles formed a platform to investigate the function of the unique mycobaterial c loop by deleting the respective loop-encoding sequence (c [166][167][168][169][170][171][172][173][174][175][176][177][178][179] ) in the genome of M. smegmatis. ATP hydrolysis-driven H + pumping was observed in IMVs containing the Dc 166-179 mutant protein but not for IMVs containing the wild-type F-ATP synthase. In addition, when compared to the wild-type enzyme, IMVs containing the Dc 166-179 mutant protein showed increased ATP cleavage and lower levels of ATP synthesis, demonstrating that the loop affects ATPase activity, ATPase-driven H + pumping and ATP synthesis. These results further indicate that the loop may affect coupling of ATP hydrolysis and synthesis in a different mode.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Deletion of a unique loop in the mycobacterial F‐ATP synthase γ subunit sheds light on its inhibitory role in ATP hydrolysis‐driven H⁺ pumping

et al. 2016

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“…Accordingt ot his strategy,w es ynthesized compounds 22 and 24.C ompound 23 was synthesized for structure-activity comparison. An antitubercular evaluation showedt hat all three compounds (22)(23)(24)f rom this series exert ar easonably potent activity against mycobacteria. Thiss uggestst hat placing frag- ment Cinthe 2-methoxyl positionm aintains the antituberculara ctivity.T he comparison of compounds 23 and 24 further reveals that the planar configuration between fragments Aa nd Bd oes not affect the antituberculara ctivity.I ta lso indicatest hat the hydroxy group is not important for the antitubercular activity of this new scaffold.…”

Section: Compounds Of Seriesmentioning

confidence: 98%

“…[11,16] Many ongoing research programsa re focused on the optimizationo fb edaquiline to decreasei ts structuralc omplexity while maintaining its antitubercular activity. [17][18][19][20][21][22][23][24] Still, new bedaquiline analoguesa re requiredt odeliver potentialnew leads. Bedaquiline (BDQ) is an ovel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013.…”

Section: Introductionmentioning

confidence: 99%

Structural Simplification of Bedaquiline: the Discovery of 3‐(4‐(N,N‐Dimethylaminomethyl)phenyl)quinoline‐Derived Antitubercular Lead Compounds

Preiß

Wang

et al. 2016

ChemMedChem

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Bedaquiline (BDQ) is a novel and highly potent last‐line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo‐structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub‐microgram per mL concentrations against both sensitive and multidrug‐resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC‐ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower‐cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non‐ATP synthase related targets.

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“…Another ATP synthase inhibitor, the substituted chloroquinoline compound 38 (161, 206) was reported to be bactericidal to hypoxic M. tuberculosis . The antimalarial drug mefloquine ( compound 39 ) was reported to kill M. tuberculosis rendered nonreplicating by hypoxia and nutrient starvation (51).…”

Section: Class II Persisters: a Majority Population Of Nonreplicatmentioning

confidence: 99%

Targeting Phenotypically TolerantMycobacterium tuberculosis

2017

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While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in a clinical setting. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of post-treatment relapse. Some promising drugs to treat tuberculosis, such as rifampicin and bedaquiline, only kill nonreplicating M. tuberculosis in vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores. However, few of these compounds were tested under conditions that would exclude the impact of adsorbed compound acting during the recovery phase of the assay, and few were tested under more than one condition imposing nonreplication. That nonreplicating mycobacteria are metabolically active was corroborated by their susceptibility to several antibiotics and tool compounds that target the synthesis of lipids, RNA, DNA, proteins, and peptidoglycan.

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Novel, potent, orally bioavailable and selective mycobacterial ATP synthase inhibitors that demonstrated activity against both replicating and non-replicating M. tuberculosis

Cited by 53 publications

References 22 publications

Deletion of a unique loop in the mycobacterial F‐ATP synthase γ subunit sheds light on its inhibitory role in ATP hydrolysis‐driven H⁺ pumping

Deletion of a unique loop in the mycobacterial F‐ATP synthase γ subunit sheds light on its inhibitory role in ATP hydrolysis‐driven H⁺ pumping

Structural Simplification of Bedaquiline: the Discovery of 3‐(4‐(N,N‐Dimethylaminomethyl)phenyl)quinoline‐Derived Antitubercular Lead Compounds

Targeting Phenotypically TolerantMycobacterium tuberculosis

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Novel, potent, orally bioavailable and selective mycobacterial ATP synthase inhibitors that demonstrated activity against both replicating and non-replicating M. tuberculosis

Cited by 53 publications

References 22 publications

Deletion of a unique loop in the mycobacterial F‐ATP synthase γ subunit sheds light on its inhibitory role in ATP hydrolysis‐driven H+ pumping

Deletion of a unique loop in the mycobacterial F‐ATP synthase γ subunit sheds light on its inhibitory role in ATP hydrolysis‐driven H+ pumping

Structural Simplification of Bedaquiline: the Discovery of 3‐(4‐(N,N‐Dimethylaminomethyl)phenyl)quinoline‐Derived Antitubercular Lead Compounds

Targeting Phenotypically TolerantMycobacterium tuberculosis

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Deletion of a unique loop in the mycobacterial F‐ATP synthase γ subunit sheds light on its inhibitory role in ATP hydrolysis‐driven H⁺ pumping

Deletion of a unique loop in the mycobacterial F‐ATP synthase γ subunit sheds light on its inhibitory role in ATP hydrolysis‐driven H⁺ pumping