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Imaging Mycobacterium tuberculosis in Mice with Reporter Enzyme Fluorescence
Published on: February 26, 2018
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Phagosomal Copper-Promoted Oxidative Attack on Intracellular Mycobacterium tuberculosis
M Daben J Libardo1, Cesar de la Fuente-Nuñez2,3,4, Kushi Anand5
1Department of Chemistry , University of Connecticut , 55 N. Eagleville Road , Storrs , Connecticut 06269 , United States.
ACS Infectious Diseases
|August 25, 2018
Summary
A novel peptide, DAB-10, creates copper-dependent oxidative stress in Mycobacterium tuberculosis, enhancing macrophage antimicrobial activity. This approach offers a new strategy for developing next-generation antimicrobials against bacterial infections.
Area of Science:
- Microbiology
- Immunology
- Drug Discovery
Background:
- Copper ions play a crucial role in controlling bacterial infections.
- Pathogens like Mycobacterium tuberculosis (Mtb) have evolved resistance mechanisms to copper.
- Developing novel antimicrobial strategies targeting bacterial copper metabolism is essential.
Purpose of the Study:
- To investigate the potential of a novel peptide, DAB-10, in generating a copper hypersensitivity phenotype in mycobacteria.
- To explore DAB-10's mechanism of action in inducing intramycobacterial oxidative stress.
- To evaluate DAB-10's efficacy in enhancing macrophage-mediated killing of Mtb.
Main Methods:
- Generating a copper hypersensitivity phenotype in mycobacteria using DAB-10.
- Assessing DAB-10's ability to induce reactive oxygen species (ROS) upon copper binding.
- Evaluating DAB-10's penetration into murine macrophages and interaction with intracellular Mtb.
- Investigating the effects of DAB-10 and a copper chelator on intracellular Mtb.
Main Results:
- DAB-10 successfully generated a copper hypersensitivity phenotype in mycobacteria, including Mtb.
- DAB-10 induced intramycobacterial oxidative stress in a copper-dependent manner, both in vitro and during infection.
- DAB-10 penetrated murine macrophages and exerted intracellular effects on Mtb.
- Co-treatment with DAB-10 and a copper chelator demonstrated significant intracellular copper-dependent protection against Mtb.
Conclusions:
- DAB-10 augments macrophage antimycobacterial activity by utilizing phagosomal copper ions.
- DAB-10 exploits Mtb's susceptibility to reactive oxygen species (ROS).
- DAB-10 serves as a model for developing next-generation, multifunctional antimicrobials targeting bacterial infections.
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