Phagosomal Copper-Promoted Oxidative Attack on Intracellular Mycobacterium tuberculosis

Libardo, Daben MJ and de la Fuente-Nunez, Cesar and Anand, Kushi and Krishnamoorthy, Gopinath and Kaiser, Peggy and Pringle, Stephanie C and Dietz, Christopher and Pierce, Scott and Smith, Michael B and Barczak, Amy and Kaufmann, Stefan HE and Singh, Amit and Angeles-Boza, Alfredo M (2018) Phagosomal Copper-Promoted Oxidative Attack on Intracellular Mycobacterium tuberculosis. In: ACS INFECTIOUS DISEASES, 4 (11). pp. 1623-1634.

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Abstract

Copper (Cu) ions are critical in controlling bacterial infections, and successful pathogens like Mycobacterium tuberculosis (Mtb) possess multiple Cu resistance mechanisms. We report, as proof of concept, that a novel Cu hypersensitivity phenotype can be generated in mycobacteria, including Mtb, through a peptide, DAB-10, that is able to form reactive oxygen species (ROS) following Cu-binding. DAB-10 induces intramycobacterial oxidative stress in a Cu-dependent manner in vitro and during infection. DAB-10 penetrates murine macrophages and encounters intracellular mycobacteria. Significant intracellular Cu-dependent protection was observed when Mtb-infected macrophages were treated with DAB-10 alongside a cell-permeable Cu chelator. Treatment with the Cu chelator reversed the intramycobacterial oxidative shift induced by DAB-10. We conclude that DAB-10 utilizes the pool of phagosomal Cu ions in the host-Mtb interface to augment the mycobactericidal activity of macrophages while simultaneously exploiting the susceptibility of Mtb to ROS. DAB-10 serves as a model with which to develop next-generation, multifunctional antimicrobials.

Item Type:	Journal Article
Publication:	ACS INFECTIOUS DISEASES
Publisher:	AMER CHEMICAL SOC
Additional Information:	Copyright of this article belongs to AMER CHEMICAL SOC
Keywords:	antimicrobial; peptide; bioinorganic chemistry; mycobactericidal; copper binding; tuberculosis
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	03 Jan 2019 10:26
Last Modified:	03 Jan 2019 10:26
URI:	http://eprints.iisc.ac.in/id/eprint/61247

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