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Inhibition of bacterial and fungal pathogens by the orphaned drug auranofin.

ABSTRACT: We identified auranofin as an antimicrobial compound utilizing a high-throughput screen using a Caenorhabditis elegans-Staphylococcus aureus infection model. Results/methodology: Treatment of infected nematodes with auranofin resulted in a prolonged survival rate of 95%, reached with 0.78 ?g/ml. Further investigation of the antimicrobial activity of auranofin found inhibition against S. aureus, Enterococcus faecium and Enterococcus faecalis. Importantly, the fungal pathogens Cryptococcus neoformans was also effectively inhibited with an MIC at 0.5 ?g/ml. Auranofin appears to target the thioredoxin system.This work provides extensive additional data on the antibacterial effects of auranofin that includes both reference and clinical isolates and reports a novel inhibition of fungal pathogens by this compound.

SUBMITTER: Fuchs BB

PROVIDER: S-EPMC4976847 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Inhibition of bacterial and fungal pathogens by the orphaned drug auranofin.

Fuchs Beth Burgwyn BB RajaMuthiah Rajmohan R Souza Ana Carolina Remondi AC Eatemadpour Soraya S Rossoni Rodnei Dennis RD Santos Daniel Assis DA Junqueira Juliana C JC Rice Louis B LB Mylonakis Eleftherios E

Future medicinal chemistry 20160125 2

<h4>Background</h4>We identified auranofin as an antimicrobial compound utilizing a high-throughput screen using a Caenorhabditis elegans-Staphylococcus aureus infection model. Results/methodology: Treatment of infected nematodes with auranofin resulted in a prolonged survival rate of 95%, reached with 0.78 μg/ml. Further investigation of the antimicrobial activity of auranofin found inhibition against S. aureus, Enterococcus faecium and Enterococcus faecalis. Importantly, the fungal pathogens C ...[more]

PMID: 26808006

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Project description:Symbiotic bacteria may dampen the impacts of infectious diseases on hosts by inhibiting pathogen growth. However, our understanding of the generality of pathogen inhibition by different bacterial taxa across pathogen genotypes and environmental conditions is limited. Bacterial inhibitory properties are of particular interest for the amphibian-killing fungal pathogens (Batrachochytrium dendrobatidis and Batrachochytrium salamandrivorans), for which probiotic applications as conservation strategies have been proposed. We quantified the inhibition strength of five putatively B. dendrobatidis-inhibitory bacteria isolated from woodland salamander skin against six Batrachochytrium genotypes at two temperatures (12 and 18°C). We selected six genotypes from across the Batrachochytrium phylogeny: B. salamandrivorans, B. dendrobatidis-Brazil and four genotypes of the B. dendrobatidis Global Panzootic Lineage (GPL1: JEL647, JEL404; GPL2: SRS810, JEL423). We performed 96-well plate challenge assays in a full factorial design. We detected a Batrachochytrium genotype by temperature interaction on bacterial inhibition score for all bacteria, indicating that bacteria vary in ability to inhibit Batrachochytrium depending on pathogen genotype and temperature. Acinetobacter rhizosphaerae moderately inhibited B. salamandrivorans at both temperatures (? = 46-53%), but not any B. dendrobatidis genotypes. Chryseobacterium sp. inhibited three Batrachochytrium genotypes at both temperatures (? = 5-71%). Pseudomonas sp. strain 1 inhibited all Batrachochytrium genotypes at 12°C and four Batrachochytrium genotypes at 18°C (? = 5-100%). Pseudomonas sp. strain 2 and Stenotrophomonas sp. moderately to strongly inhibited all six Batrachochytrium genotypes at both temperatures (? = 57-100%). All bacteria consistently inhibited B. salamandrivorans. Using cluster analysis of inhibition scores, we found that more closely related Batrachochytrium genotypes grouped together, suggesting that bacterial inhibition strength may be predictable based on Batrachochytrium relatedness. We conclude that bacterial inhibition capabilities change among bacterial strains, Batrachochytrium genotypes and temperatures. A comprehensive understanding of bacterial inhibitory function, across pathogen genotypes and temperatures, is needed to better predict the role of bacterial symbionts in amphibian disease ecology. For targeted conservation applications, we recommend using bacterial strains identified as strongly inhibitory as they are most likely to produce broad-spectrum antimicrobial agents at a range of temperatures.

Project description:BACKGROUND: The prevalence of invasive fungal infections (IFIs) has increased steadily worldwide in the last few decades. Particularly, there has been a global rise in the number of infections among immunosuppressed people. These patients present severe clinical forms of the infections, which are commonly fatal, and they are more susceptible to opportunistic fungal infections than non-immunocompromised people. IFIs have historically been associated with high morbidity and mortality, partly because of the limitations of available antifungal therapies, including side effects, toxicities, drug interactions and antifungal resistance. Thus, the search for alternative therapies and/or the development of more specific drugs is a challenge that needs to be met. Genomics has created new ways of examining genes, which open new strategies for drug development and control of human diseases. RESULTS: In silico analyses and manual mining selected initially 57 potential drug targets, based on 55 genes experimentally confirmed as essential for Candida albicans or Aspergillus fumigatus and other 2 genes (kre2 and erg6) relevant for fungal survival within the host. Orthologs for those 57 potential targets were also identified in eight human fungal pathogens (C. albicans, A. fumigatus, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Paracoccidioides lutzii, Coccidioides immitis, Cryptococcus neoformans and Histoplasma capsulatum). Of those, 10 genes were present in all pathogenic fungi analyzed and absent in the human genome. We focused on four candidates: trr1 that encodes for thioredoxin reductase, rim8 that encodes for a protein involved in the proteolytic activation of a transcriptional factor in response to alkaline pH, kre2 that encodes for ?-1,2-mannosyltransferase and erg6 that encodes for ?(24)-sterol C-methyltransferase. CONCLUSIONS: Our data show that the comparative genomics analysis of eight fungal pathogens enabled the identification of four new potential drug targets. The preferred profile for fungal targets includes proteins conserved among fungi, but absent in the human genome. These characteristics potentially minimize toxic side effects exerted by pharmacological inhibition of the cellular targets. From this first step of post-genomic analysis, we obtained information relevant to future new drug development.

Dataset Information

Inhibition of bacterial and fungal pathogens by the orphaned drug auranofin.

Publications

Inhibition of bacterial and fungal pathogens by the orphaned drug auranofin.

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