Phagosomal Copper-Promoted Oxidative Attack on Intracellular Mycobacterium tuberculosis

ACS Infectious Diseases
M Daben J LibardoAlfredo M Angeles-Boza

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.

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Citations

Mar 12, 2019·Metallomics : Integrated Biometal Science·Cameron L CrawfordFrank Wolschendorf
Aug 19, 2020·FEBS Letters·Mohammed Yousuf AnsariShekhar C Mande
Feb 2, 2021·Chemical Reviews·Jasmin PortelinhaAlfredo M Angeles-Boza
Nov 5, 2020·International Journal of Molecular Sciences·Alexander I KostyukDmitry S Bilan
Feb 21, 2021·Journal of Inorganic Biochemistry·Joanna WątłyMagdalena Rowińska-Żyrek
Jan 16, 2021·ACS Infectious Diseases·Moshe N GoldmeierTimor Baasov
Dec 21, 2019·Journal of Natural Products·Pavan K BangaloreSrinivas Kantevari

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