Developing drugs targeting transition metal homeostasis

Weekley, Claire M.; He, Chuan

doi:10.1016/j.cbpa.2016.12.011

Cited by 74 publications

(47 citation statements)

References 51 publications

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“…Many pathogens, however, produce multiple siderophores, diminishing the efficacy of any single inhibitor (37). Our work further supports that direct chelation of metal ions can simultaneously alter metal availability and interfere with essential metalloprotein-dependent cellular processes; such effects have been reported for metal chelators in targeting bacterial infections, cancer, and neurodegenerative disorders (38,39). This multifaceted strategy decreases the likelihood of bacterial resistance.…”

Section: Resultssupporting

confidence: 73%

Role for dithiolopyrrolones in disrupting bacterial metal homeostasis

Chan

Shiver

Wever

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

122

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Natural products harbor unique and complex structures that provide valuable antibiotic scaffolds. With an increase in antibiotic resistance, natural products once again hold promise for new antimicrobial therapies, especially those with unique scaffolds that have been overlooked due to a lack of understanding of how they function. Dithiolopyrrolones (DTPs) are an underexplored class of disulfide-containing natural products, which exhibit potent antimicrobial activities against multidrug-resistant pathogens. DTPs were thought to target RNA polymerase, but conflicting observations leave the mechanisms elusive. Using a chemical genomics screen in , we uncover a mode of action for DTPs-the disruption of metal homeostasis. We show that holomycin, a prototypical DTP, is reductively activated, and reduced holomycin chelates zinc with high affinity. Examination of reduced holomycin against zinc-dependent metalloenzymes revealed that it inhibits class II fructose bisphosphate aldolase, but not RNA polymerase. Reduced holomycin also strongly inhibits metallo-β-lactamases in vitro, major contributors to clinical carbapenem resistance, by removing active site zinc. These results indicate that holomycin is an intracellular metal-chelating antibiotic that inhibits a subset of metalloenzymes and that RNA polymerase is unlikely to be the primary target. Our work establishes a link between the chemical structures of DTPs and their antimicrobial action; the ene-dithiol group of DTPs enables high-affinity metal binding as a central mechanism to inhibit metabolic processes. Our study also validates the use of chemical genomics in characterizing modes of actions of antibiotics and emphasizes the potential of metal-chelating natural products in antimicrobial therapy.

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Section: Resultssupporting

confidence: 73%

Role for dithiolopyrrolones in disrupting bacterial metal homeostasis

Chan

Shiver

Wever

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

122

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“…Current approaches to targeting copper homeostasis include the inhibition of copper-dependent enzymes by global copper chelation, and the use of copper ionophores to elevate or redistribute copper and overwhelm the antioxidant capacity of cancer cells (22). Recently, the chelator tetrathiomolybdate (TM) was evaluated in a Phase II clinical trial for patients with breast cancer with high risk of recurrence.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Copper Transport Induces Apoptosis in Triple-Negative Breast Cancer Cells and Suppresses Tumor Angiogenesis

Karginova

Weekley

Raoul

et al. 2019

Molecular Cancer Therapeutics

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Treatment of advanced breast cancer remains challenging. Copper and some of the copper-dependent proteins are emerging therapeutic targets because they are essential for cell proliferation and survival, and have been shown to stimulate angiogenesis and metastasis. Here, we show that DCAC50, a recently developed small-molecule inhibitor of the intracellular copper chaperones, ATOX1 and CCS, reduces cell proliferation and elevates oxidative stress, triggering apoptosis in a panel of triple-negative breast cancer (TNBC) cells. Inhibition of ATOX1 activity with DCAC50 disrupts copper homeostasis, leading to increased copper levels, altered spatial copper redistribution, and accumula-tion of ATP7B to the cellular perinuclear region. The extent and impact of this disruption to copper homeostasis vary across cell lines and correlate with cellular baseline copper and glutathione levels. Ultimately, treatment with DCAC50 attenuates tumor growth and suppresses angiogenesis in a xenograft mouse model, and prevents endothelial cell network formation in vitro. Co-treatment with paclitaxel and DCAC50 enhances cytotoxicity in TNBC and results in favorable dose reduction of both drugs. These data demonstrate that inhibition of intracellular copper transport targets tumor cells and the tumor microenvironment, and is a promising approach to treat breast cancer.

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“…The toxicity of and pathways involved in metal imbalances are now considered to be highly active areas of biomedical research. The findings of these studies might inspire us to develop new classes of therapeutic strategies and help us to understand metal metabolism [5,6].…”

Section: Introductionmentioning

confidence: 99%

Genetic Disorders Associated with Metal Metabolism

Umair

Alfadhel

2019

Cells

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Genetic disorders associated with metal metabolism form a large group of disorders and mostly result from defects in the proteins/enzymes involved in nutrient metabolism and energy production. These defects can affect different metabolic pathways and cause mild to severe disorders related to metal metabolism. Some disorders have moderate to severe clinical consequences. In severe cases, these elements accumulate in different tissues and organs, particularly the brain. As they are toxic and interfere with normal biological functions, the severity of the disorder increases. However, the human body requires a very small amount of these elements, and a deficiency of or increase in these elements can cause different genetic disorders to occur. Some of the metals discussed in the present review are copper, iron, manganese, zinc, and selenium. These elements may play a key role in the pathology and physiology of the nervous system.

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Developing drugs targeting transition metal homeostasis

Cited by 74 publications

References 51 publications

Role for dithiolopyrrolones in disrupting bacterial metal homeostasis

Role for dithiolopyrrolones in disrupting bacterial metal homeostasis

Inhibition of Copper Transport Induces Apoptosis in Triple-Negative Breast Cancer Cells and Suppresses Tumor Angiogenesis

Genetic Disorders Associated with Metal Metabolism

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