|
[PMID]: | 29370698 | [Au] Autor: | Mohammad H; Elghazawy NH; Eldesouky HE; Hegazy YA; Younis W; Avrimova L; Hazbun T; Arafa RK; Seleem MN |
[Ad] Address: | Department of Comparative Pathobiology , College of Veterinary Medicine, Purdue University , 625 Harrison Street , West Lafayette , Indiana 47907 , United States. | [Ti] Title: | Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis. | [So] Source: | ACS Infect Dis;4(3):403-414, 2018 Mar 09. | [Is] ISSN: | 2373-8227 | [Cp] Country of publication: | United States | [La] Language: | eng | [Ab] Abstract: | Globally, invasive fungal infections pose a significant challenge to modern human medicine due to the limited number of antifungal drugs and the rise in resistance to current antifungal agents. A vast majority of invasive fungal infections are caused by species of Candida, Cryptococcus, and Aspergillus. Novel antifungal molecules consisting of unexploited chemical scaffolds with a unique mechanism are a pressing need. The present study identifies a dibromoquinoline compound (4b) with broad-spectrum antifungal activity that inhibits the growth of pertinent species of Candida (chiefly C. albicans), Cryptococcus, and Aspergillus at a concentration of as low as 0.5 µg/mL. Furthermore, 4b, at a subinhibitory concentration, interfered with the expression of two key virulence factors (hyphae and biofilm formation) involved in C. albicans pathogenesis. Three yeast deletion strains ( cox17Δ, ssa1Δ, and aft2Δ) related to metal ion homeostasis were found to be highly sensitive to 4b in growth assays, indicating that the compound exerts its antifungal effect through a unique, previously unexploited mechanism. Supplementing the media with either copper or iron ions reversed the strain sensitivity to 4b, further corroborating that the compound targets metal ion homeostasis. 4b's potent antifungal activity was validated in vivo, as the compound enhanced the survival of Caenorhabditis elegans infected with fluconazole-resistant C. albicans. The present study indicates that 4b warrants further investigation as a novel antifungal agent. | [Pt] Publication type: | JOURNAL ARTICLE | [Em] Entry month: | 1801 | [Cu] Class update date: |
180309 | [Lr] Last revision date: | 180309 | [St] Status: | In-Data-Review |
[do] DOI: | 10.1021/acsinfecdis.7b00215 |
|