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Related Concept Videos

ATP Synthase: Mechanism01:48

ATP Synthase: Mechanism

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In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
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Targets for Drug Action: Overview01:26

Targets for Drug Action: Overview

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Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
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The Electron Transport Chain01:30

The Electron Transport Chain

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The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...
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ABC Transporters: Importer01:27

ABC Transporters: Importer

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ATP-binding cassette or ABC transporters are a class of ATP-driven pumps that hydrolyze ATP to move solutes across the membrane. They can be grouped into importers and exporters. While exporters are present in all domains of life, importers exist only in bacteria and some plants.
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Pulmonary Tuberculosis V01:28

Pulmonary Tuberculosis V

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Medical management of tuberculosis (TB) patients involves a comprehensive approach that includes diagnosis, treatment, and monitoring. The specific strategies can vary depending on the type of tuberculosis (latent or active), the patient's overall health status, and other considerations.
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ATP Synthase: Structure01:18

ATP Synthase: Structure

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ATP synthase or ATPase is among the most conserved proteins found in bacteria, mammals, and plants. This enzyme can catalyze a forward reaction in response to the electrochemical gradient, producing ATP from ADP and inorganic phosphate. ATP synthase can also work in a reverse direction by hydrolyzing ATP and generating an electrochemical gradient. Different forms of ATP synthases have evolved special features to meet the specific demands of the cell. Based on their specific feature, ATP...
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Related Experiment Video

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System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis
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System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis

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Mycobacterium tuberculosis F-ATP Synthase Inhibitors and Targets.

Amaravadhi Harikishore1, Gerhard Grüber1

  • 1School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.

Antibiotics (Basel, Switzerland)
|January 8, 2025
PubMed
Summary

Mycobacterium tuberculosis (Mtb) uses dormant survival strategies and alternative metabolism to resist drugs. New inhibitors targeting F1F0-ATP synthase offer hope against tuberculosis (TB).

Keywords:
ETC (electron transport chain)F-ATP synthaseOXPHOSbedaquilineinhibitorsmycobacteria

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A High-throughput Compatible Assay to Evaluate Drug Efficacy against Macrophage Passaged Mycobacterium tuberculosis
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Area of Science:

  • Microbiology
  • Biochemistry
  • Drug Discovery

Background:

  • Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a major global health threat with over 1.13 million annual deaths.
  • Mtb employs dormancy and non-canonical regulatory mechanisms, including alternative oxidase pathways, to survive harsh conditions and establish latent infections.
  • Drug resistance in Mtb arises from mutations, enzyme overexpression, and efflux pumps, complicating treatment.

Purpose of the Study:

  • To review non-canonical structural and regulatory epitopes of the Mtb F1-domain.
  • To discuss ligand development targeting these sites.
  • To explore inhibitors of the F0-domain and Mtb's adaptive respiratory responses to bedaquiline.

Main Methods:

  • Literature review focusing on Mtb survival mechanisms and F1F0-ATP synthase inhibitors.
  • Analysis of non-canonical structural and regulatory pathogen-specific epitopes.
  • Examination of inhibitor classes and Mtb's metabolic adaptations.

Main Results:

  • Bedaquiline and its analogs are potent inhibitors of Mtb F1F0-ATP synthase in both replicating and non-replicating forms.
  • Oxidative phosphorylation is a viable target for anti-TB therapies.
  • Mtb utilizes alternative respiratory pathways to survive bedaquiline treatment and establish latency.

Conclusions:

  • Targeting Mtb's F1F0-ATP synthase and understanding its adaptive survival strategies are crucial for developing new anti-TB drugs.
  • Novel inhibitors and insights into Mtb's metabolic flexibility are essential for combating drug-resistant tuberculosis.