Phagosomal Copper-Promoted Oxidative Attack on Intracellular Mycobacterium tuberculosis

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.

Dynamics of plasma micronutrient concentrations and their correlation with serum proteins and thyroid hormones in patients with paracoccidioidomycosis

“…Alternately, similar findings to those from our study have been reported, including detection of high serum levels of copper during the initial phase of other chronic infectious diseases [31, 33]. Copper ions have been observed to be crucial for the control of intracellular bacteria by optimizing their oxidative attack on Mycobacterium tuberculosis within macrophagic phagolysosomes [34]. Thus, elevated levels could indicate an attempt by the patient’s immune system to control Paracoccidioides spp.…”

Coordination Complexes to Combat Bacterial Infections: Recent Developments, Current Directions and Future Opportunities

“…The peptide sequence enables efficient permeation into the cytoplasm of M. tuberculosis which resides in the phagosome of infected macrophages. Once accumulated in the phagosome, the conjugate binds abundant Cu 2+ to afford Cu(ATCUN)‐AMP [86] . The Cu(ATCUN) complex generates ROS efficiently, producing more oxidative stress and a bactericidal effect superseding the activity of homologous AMP peptides without the ATCUN motif.…”

A novel function of Mycobacterium tuberculosis chaperonin paralog GroEL1 in copper homeostasis

“…The first insight into the role of copper at the host‐pathogen interface was reported by the finding that copper level fluctuated from 25 to 500 µ m in the phagosome infected with M. tuberculosis [4]. Recently it has been reported that utilizing abundance of copper ions in the M. tuberculosis infected phagosome using peptide that binds copper ions and mediates generation of reactive oxygen species by exploiting the redox property of copper ions [55]. We used mycobacterial strains containing groEL1 ‐WT, groEL1 ‐KO and groEL1 ‐Comp (complemented) gene to study effect of copper on survival at different concentrations.…”