Metalloproteomics in conjunction with other omics for uncovering the mechanism of action of metallodrugs: Mechanism-driven new therapy development

Weng, Haibo; Zhou, Ying; Xu, Xiaohan; Li, Hongyan; Sun, Hongzhe

doi:10.1016/j.cbpa.2020.02.006

Cited by 55 publications

(35 citation statements)

References 55 publications

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“…Up to now, most studies focus on the up- and down-regulated proteins in S. aureus post exposure to Ag + or AgNPs by quantitative proteomic approaches 26 , 27 . However, no proteins that directly bind Ag + have been identified in S. aureus systematically owing to the complexity of metal–protein interactions in cells and the chemistry of Ag + as well as a lack of appropriate techniques, which hinders in-depth understanding the mode of action of antibacterial silver 28 – 30 . Several approaches, e.g., laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) 31 , liquid chromatography hyphenated with ICP-MS 32 , 33 , synchrotron X-ray fluorescence spectrometry (SXFS) 34 , and fluorescence labeling 19 , 35 , have been developed to mine unknown metalloproteomes in microbes.…”

Section: Introductionmentioning

confidence: 99%

Multi-target mode of action of silver against Staphylococcus aureus endows it with capability to combat antibiotic resistance

Wang

et al. 2021

Nat Commun

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115

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The rapid emergence of drug resistant Staphylococcus aureus (S. aureus) poses a serious threat to public health globally. Silver (Ag)-based antimicrobials are promising to combat antibiotic resistant S. aureus, yet their molecular targets are largely elusive. Herein, we separate and identify 38 authentic Ag+-binding proteins in S. aureus at the whole-cell scale. We then capture the molecular snapshot on the dynamic action of Ag+ against S. aureus and further validate that Ag+ could inhibit a key target 6-phosphogluconate dehydrogenase through binding to catalytic His185 by X-ray crystallography. Significantly, the multi-target mode of action of Ag+ (and nanosilver) endows its sustainable antimicrobial efficacy, leading to enhanced efficacy of conventional antibiotics and resensitization of MRSA to antibiotics. Our study resolves the long-standing question of the molecular targets of silver in S. aureus and offers insights into the sustainable bacterial susceptibility of silver, providing a potential approach for combating antimicrobial resistance.

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Section: Introductionmentioning

confidence: 99%

Multi-target mode of action of silver against Staphylococcus aureus endows it with capability to combat antibiotic resistance

Wang

et al. 2021

Nat Commun

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115

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“…Up and down regulated cellular proteins due to effects of drug and molecular targets interactions, identified and quantified by proteomics, together with cell uptake and subcellular distribution, quantified by metallomics, and changes in gene expression, determined by transcriptomics, allow to get a deeper insight into what occurs in the cells after administering a metallodrug. The knowledge achieved is a useful income for the rational design of novel metallodrugs (Wang et al, 2020).…”

Section: Ferrocenyl Derivativesmentioning

confidence: 99%

Facing Diseases Caused by Trypanosomatid Parasites: Rational Design of Pd and Pt Complexes With Bioactive Ligands

Gambino

Otero

2022

Front. Chem.

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Human African Trypanosomiasis (HAT), Chagas disease or American Trypanosomiasis (CD), and leishmaniases are protozoan infections produced by trypanosomatid parasites belonging to the kinetoplastid order and they constitute an urgent global health problem. In fact, there is an urgent need of more efficient and less toxic chemotherapy for these diseases. Medicinal inorganic chemistry currently offers an attractive option for the rational design of new drugs and, in particular, antiparasitic ones. In this sense, one of the main strategies for the design of metal-based antiparasitic compounds has been the coordination of an organic ligand with known or potential biological activity, to a metal centre or an organometallic core. Classical metal coordination complexes or organometallic compounds could be designed as multifunctional agents joining, in a single molecule, different chemical species that could affect different parasitic targets. This review is focused on the rational design of palladium(II) and platinum(II) compounds with bioactive ligands as prospective drugs against trypanosomatid parasites that has been conducted by our group during the last 20 years.

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“…Given that metalloanticancer drugs often act on various targets through multifaceted mechanisms, [22][23][24] understanding their modes of action may in turn extend their pharmaceutical potential. [25][26][27] For example, the combination of two or more therapeutic interventions that have distinctive mechanisms of action can minimize the development of drug resistance and reduce severe side effects. 28 It has been reported that ZIO-101 exerts its therapeutic effects by inducing apoptosis in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Dynamic and Temporal Transcriptomic Analysis Reveals Ferroptosis-Mediated Antileukemia Activity of S-Dimethylarsino-Glutathione: Insights into Novel Therapeutic Strategy

Wang

et al. 2022

CCS Chem

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S-dimethylarsino-glutathione (ZIO-101, darinapar-sin®) exhibits broader antitumor activity and less toxicity than arsenic trioxide (ATO), a clinically used drug for acute promyelocytic leukemia (APL) treatment. However, the mechanisms of action underlying antileukemia activities of ZIO-101 remain largely unknown. Herein, by integrating dynamic transcriptomic analysis and biochemical characterizations, we for the first time delineated that ZIO-101 exerted antiproliferative effects against leukemia cells via activating ferroptosis pathway, a newly discovered iron-dependent programmed cell death, at the early stage, as evidenced by abnormally elevated intracellular iron contents and lipid peroxidation. We further demonstrated that silencing heme oxygenase 1 (HMOX1), an important iron homeostasis-related gene, effectively attenuated ferroptosis induced by ZIO-101, with iron accumulation and lipid peroxidation being significantly alleviated. Significantly, we discovered that ZIO-101 and kinase inhibitors (Dasatinib/Dactolisib) could synergistically kill leukemia cells, with a combination index of <1.0 under all the tested drug concentrations. Our findings regarding the ferroptosis-mediated antileukemia activity of ZIO-101, based on the dynamic and temporal transcriptomic analysis, provide promising approaches to combat drug-resistant leukemia by combining ZIO-101 with kinase inhibitors. The methodology may be further exploited for uncovering the modes of action of other drugs.

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Metalloproteomics in conjunction with other omics for uncovering the mechanism of action of metallodrugs: Mechanism-driven new therapy development

Cited by 55 publications

References 55 publications

Multi-target mode of action of silver against Staphylococcus aureus endows it with capability to combat antibiotic resistance

Multi-target mode of action of silver against Staphylococcus aureus endows it with capability to combat antibiotic resistance

Facing Diseases Caused by Trypanosomatid Parasites: Rational Design of Pd and Pt Complexes With Bioactive Ligands

Dynamic and Temporal Transcriptomic Analysis Reveals Ferroptosis-Mediated Antileukemia Activity of S-Dimethylarsino-Glutathione: Insights into Novel Therapeutic Strategy

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