Recent advancements in mechanistic studies and structure activity relationship of FoF1 ATP synthase inhibitor as antimicrobial agent

Narang, Rakesh; Kumar, Raj; Kalra, Sourav; Nayak, Satheesha B; Khatik, Gopal L.; Kumar, Gadekula Naresh; Sudhakar, Kalvatala; Singh, Sachin Kumar

doi:10.1016/j.ejmech.2019.111644

Cited by 24 publications

(13 citation statements)

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“…Haagsma's group showed that ATP synthase isolated from human, mouse, and bovine mitochondria displayed extremely lower sensitivity for bedaquiline compared to that of mycobacterial ATP synthase (Haagsma et al, 2009), which indicates that bedaquiline is able to selectively inhibit ATP synthase in bacteria but not in mitochondria of normal cells (Fiorillo et al, 2016). This property contributes to its clinical usage as antibacterial agent due to toxicity issues and fatality concerns (Ferlazzo et al, 2018;Narang et al, 2019). Therefore, the potent inhibitory effect of bedaquiline on oral microorganisms and the non-toxic effect on PDLSCs in the present study laid a solid foundation for bedaquiline as a novel anti-caries agent.…”

Section: Discussionmentioning

confidence: 99%

“…During our continuous search for potential anti-caries agent, we identified bedaquiline, an antibiotic that was initially developed to specifically inhibit the mycobacterial ATP-synthase (Preiss et al, 2015) and does not recruit ATP synthesis-related toxicity in mammalian cells (Haagsma et al, 2009;Narang et al, 2019). The strong inhibitory effect of bedaquiline on Streptococcus mutans confirmed in preliminary experiments led us to propose that bedaquiline could be repurposed as a novel anti-caries agent, for the targeting H + -ATPase.…”

Section: Introductionmentioning

confidence: 99%

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In vitro Antibacterial Activity of an FDA-Approved H+-ATPase Inhibitor, Bedaquiline, Against Streptococcus mutans in Acidic Milieus

Zhang

Zhou

et al. 2021

Front. Microbiol.

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BackgroundDental caries is an acid-related disease. Current anti-caries agents mainly focus on the bacteriostatic effect in a neutral environment and do not target acid-resistant microorganisms related to caries in acidic milieus.ObjectivesTo assess the in vitro antibacterial activities of bedaquiline against oral pathogens in acidic milieus.MethodsStreptococcus mutans, Streptococcus sanguinis, and Streptococcus salivarius were used to prepare the mono-/multiple suspension and biofilm. The MIC and IC50 of bedaquiline against S. mutans were determined by the broth microdilution method. Bedaquiline was compared regarding (i) the inhibitory activity in pH 4–7 and at different time points against planktonic and biofilm; (ii) the effect on the production of lactic acid, extracellular polysaccharide, and pH of S. mutans biofilm; (iii) the cytotoxicity effects; and (iv) the activity on H+-ATPase enzyme of S. mutans.ResultsIn pH 5 BHI, 2.5 mg/L (IC50) and 4 mg/L (MIC) of bedaquiline inhibited the proliferation and biofilm generation of S. mutans and Mix in a dose-dependent and time-dependent manner, but it was invalid in a neutral environment. The lactic acid production, polysaccharide production, and pH drop range reduced with the incorporation of bedaquiline in a pH 5 environment. Its inhibitory effect (>56 mg/L) against H+-ATPase enzyme in S. mutans and its non-toxic effect (<10 mg/L) on periodontal ligament stem cells were also confirmed.ConclusionBedaquiline is efficient in inhibiting the proliferation and biofilm generation of S. mutans and other oral pathogens in an acidic environment. Its high targeting property and non-cytotoxicity also promote its clinical application potential in preventing caries. Further investigation of its specific action sites and drug modification are warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In vitro Antibacterial Activity of an FDA-Approved H+-ATPase Inhibitor, Bedaquiline, Against Streptococcus mutans in Acidic Milieus

Zhang

Zhou

et al. 2021

Front. Microbiol.

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“…Although the F O F 1 -ATP synthase complex is inhibited by over 250 natural and synthetic inhibitors, the number of peptide-like inhibitors reported so far is relatively low [55]. Most of these peptides with promising pharmaceutical activities coming from exogenous natural sources such as venoms, sponges, and insects have been reported as inhibitors of EcF 1 [56][57][58][59].…”

Section: Discussionmentioning

confidence: 99%

Engineering protein fragments via evolutionary and protein–protein interaction algorithms: de novo design of peptide inhibitors for F_OF₁‐ATP synthase

et al. 2020

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Enzyme subunit interfaces have remarkable potential in drug design as both target and scaffold for their own inhibitors. We show an evolution‐driven strategy for the de novo design of peptide inhibitors targeting interfaces of the Escherichia coli FoF1‐ATP synthase as a case study. The evolutionary algorithm ROSE was applied to generate diversity‐oriented peptide libraries by engineering peptide fragments from ATP synthase interfaces. The resulting peptides were scored with PPI‐Detect, a sequence‐based predictor of protein–protein interactions. Two selected peptides were confirmed by in vitro inhibition and binding tests. The proposed methodology can be widely applied to design peptides targeting relevant interfaces of enzymatic complexes.

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“…This depends on target-based accumulation of BDQ and leads to an uncoupled microenvironment around the F 1 F o -ATP synthase . Several new inhibitors of the mycobacterial F 1 F o -ATP synthase have been identified (Singh et al, 2015;Tantry et al, 2017;Narang et al, 2019;Kamariah et al, 2020;Hards et al, 2022). However, further studies are needed to determine their clinical safety and efficacy.…”

Section: Mycobacterial F 1 F O Atp Synthasementioning

confidence: 99%

Uncovering interactions between mycobacterial respiratory complexes to target drug-resistant Mycobacterium tuberculosis

McNeil

Cheung

Waller

et al. 2022

Front. Cell. Infect. Microbiol.

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Mycobacterium tuberculosis remains a leading cause of infectious disease morbidity and mortality for which new drug combination therapies are needed. Mycobacterial bioenergetics has emerged as a promising space for the development of novel therapeutics. Further to this, unique combinations of respiratory inhibitors have been shown to have synergistic or synthetic lethal interactions, suggesting that combinations of bioenergetic inhibitors could drastically shorten treatment times. Realizing the full potential of this unique target space requires an understanding of which combinations of respiratory complexes, when inhibited, have the strongest interactions and potential in a clinical setting. In this review, we discuss (i) chemical-interaction, (ii) genetic-interaction and (iii) chemical-genetic interaction studies to explore the consequences of inhibiting multiple mycobacterial respiratory components. We provide potential mechanisms to describe the basis for the strongest interactions. Finally, whilst we place an emphasis on interactions that occur with existing bioenergetic inhibitors, by highlighting interactions that occur with alternative respiratory components we envision that this information will provide a rational to further explore alternative proteins as potential drug targets and as part of unique drug combinations.

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Recent advancements in mechanistic studies and structure activity relationship of FoF1 ATP synthase inhibitor as antimicrobial agent

Cited by 24 publications

References 113 publications

In vitro Antibacterial Activity of an FDA-Approved H+-ATPase Inhibitor, Bedaquiline, Against Streptococcus mutans in Acidic Milieus

In vitro Antibacterial Activity of an FDA-Approved H+-ATPase Inhibitor, Bedaquiline, Against Streptococcus mutans in Acidic Milieus

Engineering protein fragments via evolutionary and protein–protein interaction algorithms: de novo design of peptide inhibitors for F_OF₁‐ATP synthase

Uncovering interactions between mycobacterial respiratory complexes to target drug-resistant Mycobacterium tuberculosis

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Recent advancements in mechanistic studies and structure activity relationship of FoF1 ATP synthase inhibitor as antimicrobial agent

Cited by 24 publications

References 113 publications

In vitro Antibacterial Activity of an FDA-Approved H+-ATPase Inhibitor, Bedaquiline, Against Streptococcus mutans in Acidic Milieus

In vitro Antibacterial Activity of an FDA-Approved H+-ATPase Inhibitor, Bedaquiline, Against Streptococcus mutans in Acidic Milieus

Engineering protein fragments via evolutionary and protein–protein interaction algorithms: de novo design of peptide inhibitors for FOF1‐ATP synthase

Uncovering interactions between mycobacterial respiratory complexes to target drug-resistant Mycobacterium tuberculosis

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Product

Resources

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Engineering protein fragments via evolutionary and protein–protein interaction algorithms: de novo design of peptide inhibitors for F_OF₁‐ATP synthase