Dataset Information

Exposure of Candida parapsilosis to the silver(I) compound SBC3 induces alterations in the proteome inhibiting protein synthesis and reducing virulence

ABSTRACT: The antimicrobial properties of silver have been exploited for many centuries and continue to gain interest in the fight against antimicrobial drug resistance. The broad-spectrum activity and low toxicity of silver has led to its incorporation into a wide range of novel antimicrobial agents, including N-heterocyclic carbene (NHC) complexes. These versatile organic compounds readily bind transition metals and allow various substitutions, ring sizes and general properties. The antimicrobial activity and in vivo efficacy of the NHC silver(I) acetate complex SBC3, derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*), has previously been demonstrated, although the mode(s) of action of SBC3 remained unclear. Label-free quantitative (LFQ) proteomics was employed to analyse protein abundance changes in the yeast Candida parapsilosis in response to SBC3 treatment and gain insight into potential SBC3 targets. Proteomic analysis of C. parapsilosis following exposure to SBC3 revealed increased abundance in proteins associated with cell wall synthesis, detoxification and drug efflux that are indicative of a cell stress response. Significant decreases in proteins required for protein synthesis, amino acid biosynthesis and respiration offer potential insight into the growth-inhibitory mechanisms of SBC3. Exposure of C. parapsilosis to SBC3 lead to reduced adherence to epithelial cells and biofilm formation which may indicate the compound can reduce fungal virulence.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Candida Parapsilosis Cdc317

TISSUE(S): Cell Culture

SUBMITTER: Magdalena Piatek

LAB HEAD: Kevin Kavanagh

PROVIDER: PXD025693 | Pride | 2022-06-28

REPOSITORIES: Pride

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Publications

Exposure of Candida parapsilosis to the silver(I) compound SBC3 induces alterations in the proteome and reduced virulence.

Piatek Magdalena M O'Beirne Cillian C Beato Zoe Z Tacke Matthias M Kavanagh Kevin K

Metallomics : integrated biometal science 20220801 8

The antimicrobial properties of silver have been exploited for many centuries and continue to gain interest in the fight against antimicrobial drug resistance. The broad-spectrum activity and low toxicity of silver have led to its incorporation into a wide range of novel antimicrobial agents, including N-heterocyclic carbene (NHC) complexes. The antimicrobial activity and in vivo efficacy of the NHC silver(I) acetate complex SBC3, derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*), ...[more]

PMID: 35751649

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Project description:Emerging antibiotic resistance among clinically relevant bacteria, paired with their ability to form biofilms on medical and technical devices, represents a serious problem in terms of effective and long-term decontamination in health care environments and gives rise to an urgent need for new antimicrobial materials. Here we present the first study of the impact of AGXXÂ®, a novel broad-spectrum antimicrobial surface coating consisting of micro galvanic elements formed by silver and ruthenium, on the transcriptome of the nosocomial pathogen Enterococcus faecalis. E. faecalis was subjected to metal stress by growing it for different periods of time in the presence of AGXXÂ® or silver-coated steel meshes. Subsequently, total RNA was isolated and next-generation RNA sequencing was performed to analyze variations in gene expression levels in the presence of the antimicrobial materials with focus on known stress genes. Exposure to AGXXÂ® had a large impact on the transcriptome of E. faecalis. After 24 minutes almost 1/5 of the E. faecalis genome displayed differential expression. At each time-point the cop operon was strongly up-regulated, providing indirect evidence for the presence of free Ag+-ions. Moreover, exposure to AGXXÂ® induced a broad general stress response in E. faecalis. Genes coding for the chaperones GroEL and GroES as well as the Clp proteases ClpE and ClpB were among the top up-regulated heat shock genes. Furthermore, differential expression of genes coding for thioredoxin, superoxide dismutase and glutathione synthetase indicates a high level of oxidative stress. We postulate a mechanism of action where the combination of Ag+-ions and reactive oxygen species generated by AGXXÂ® results in a synergistic antimicrobial effect, which is superior to that of conventional silver coatings. Gene expression analysis of Enterococcus faecalis 12030 either subjected to metal stress by exposure to an antimicrobial AGXXÂ®- or Ag-coated V2A steel mesh or exposed to an uncoated V2A steel mesh or left untreated performing RNA Sequencing with an Ion ProtonTM Sequencer and subsequent data analysis with a T-REx RNA-Sequencing expression analysis pipeline.

Project description:The rapid emergence of drug resistant Staphylococcus aureus (S. aureus), in particular, methicillin-resistant S. aureus (MRSA) poses a serious threat to public health globally. Reuse of metal-based antimicrobials stands for one of the most promising strategies to resensitize drug resistant bacteria to conventional antibiotics. Silver (Ag) has been used as an antimicrobial agent since antiquity, yet its molecular mechanism of action is elusive largely owing to technical challenges to identify the direct silver-binding protein targets accountable for its action. Herein, using an in-house developed hyphenated technique LC-GE-ICP-MS, we successfully separated and identified 38 authentic Ag+-binding proteins (Ag+-proteome) in S. aureus at the whole-cell scale for the first time. By integration with bioinformatic analysis and systematic biochemical characterizations, we captured the first snapshot on the dynamic action of Ag+ against S. aureus at the molecular level, i.e., Ag+ primarily targets glycolysis via inhibiting multiple enzymes and induces the elevation of ROS through functional disruption of redox homeostasis system at the late stage, leading to an upregulation of oxidative pentose phosphate pathway (oxPPP) to alleviate Ag+ stress. However, the activation of oxPPP is ultimately futile due to key oxPPP enzymes being inhibited by Ag+. We further validated that Ag+ could inhibit 6-phosphogluconate dehydrogenase, a key target from oxPPP through binding to His185 at the active site and morphing the shape of catalytic pocket by X-ray crystallography. Significantly, the multi-target mode of action of silver is accountable for its suppression of antibiotic selection effects towards S. aureus as well as its sustainable antimicrobial activity. Such a unique mode of action of Ag+ (and silver nanoparticles) led to enhanced efficacy of a broad range of 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 a novel insight into the sustainable bacterial susceptibility of silver, providing a potential approach for combating antimicrobial resistance.

Dataset Information

Exposure of Candida parapsilosis to the silver(I) compound SBC3 induces alterations in the proteome inhibiting protein synthesis and reducing virulence

Publications

Exposure of Candida parapsilosis to the silver(I) compound SBC3 induces alterations in the proteome and reduced virulence.

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