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We identified sr7575, a molecule that inhibits growth of the evolutionary distant fungi\n A. fumigatus<\/jats:named-content>\n ,\n Cryptococcus neoformans<\/jats:named-content>\n ,\n Candida albicans<\/jats:named-content>\n , and\n Saccharomyces cerevisiae<\/jats:named-content>\n but lacks acute toxicity for mammalian cells. To gain insight into the mode of inhibition, sr7575 was screened against 4,885\n S. cerevisiae<\/jats:named-content>\n mutants from the systematic collection of haploid deletion strains and 977 barcoded haploid DAmP (decreased abundance by mRNA perturbation) strains in which the function of essential genes was perturbed by the introduction of a drug resistance cassette downstream of the coding sequence region. Comparisons with previously published chemogenomic screens revealed that the set of mutants conferring sensitivity to sr7575 was strikingly narrow, affecting components of the endoplasmic reticulum-associated protein degradation (ERAD) stress response and the ER membrane protein complex (EMC). ERAD-deficient mutants were hypersensitive to sr7575 in both\n S. cerevisiae<\/jats:named-content>\n and\n A. fumigatus<\/jats:named-content>\n , indicating a conserved mechanism of growth inhibition between yeast and filamentous fungi. Although the unfolded protein response (UPR) is linked to ERAD regulation, sr7575 did not trigger the UPR in\n A. fumigatus<\/jats:named-content>\n and UPR mutants showed no enhanced sensitivity to the compound. The data from this chemogenomic analysis demonstrate that sr7575 exerts its antifungal activity by disrupting ER protein quality control in a manner that requires ERAD intervention but bypasses the need for the canonical UPR. ER protein quality control is thus a specific vulnerability of fungal organisms that might be exploited for antifungal drug development.\n <\/jats:p>","DOI":"10.1128\/aac.02239-15","type":"journal-article","created":{"date-parts":[[2015,12,15]],"date-time":"2015-12-15T04:43:50Z","timestamp":1450154630000},"page":"1438-1449","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":9,"title":["The Toxicity of a Novel Antifungal Compound Is Modulated by Endoplasmic Reticulum-Associated Protein Degradation Components"],"prefix":"10.1128","volume":"60","author":[{"given":"Shriya","family":"Raj","sequence":"first","affiliation":[{"name":"Institut Pasteur, Unit\u00e9 des Aspergillus, D\u00e9partement Mycologie, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karthik","family":"Krishnan","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, University of 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