دورية أكاديمية
أعرض في EDS

Proteomics reveals that the antifungal activity of fenbendazole against Cryptococcus neoformans requires protein kinases.

التفاصيل البيبلوغرافية
العنوان: Proteomics reveals that the antifungal activity of fenbendazole against Cryptococcus neoformans requires protein kinases.
المؤلفون: de Oliveira HC; Instituto Carlos Chagas, Fundação Oswaldo Cruz (Fiocruz), Curitiba, Brazil., Santos MDM; Instituto Carlos Chagas, Fundação Oswaldo Cruz (Fiocruz), Curitiba, Brazil; Analytical Biochemistry and Proteomics Unit. IIBCE/Institut Pasteur de Montevideo, Uruguay., Camillo-Andrade AC; Instituto Carlos Chagas, Fundação Oswaldo Cruz (Fiocruz), Curitiba, Brazil; Analytical Biochemistry and Proteomics Unit. IIBCE/Institut Pasteur de Montevideo, Uruguay., Castelli RF; Instituto Carlos Chagas, Fundação Oswaldo Cruz (Fiocruz), Curitiba, Brazil., Dos Reis FCG; Instituto Carlos Chagas, Fundação Oswaldo Cruz (Fiocruz), Curitiba, Brazil; Centro de Desenvolvimento Tecnológico em Saúde (CDTS), Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Carvalho PC; Instituto Carlos Chagas, Fundação Oswaldo Cruz (Fiocruz), Curitiba, Brazil., Rodrigues ML; Instituto Carlos Chagas, Fundação Oswaldo Cruz (Fiocruz), Curitiba, Brazil; Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: marcio.rodrigues@fiocruz.br.
المصدر: International journal of antimicrobial agents [Int J Antimicrob Agents] 2024 May; Vol. 63 (5), pp. 107157. Date of Electronic Publication: 2024 Mar 26.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Publishers Country of Publication: Netherlands NLM ID: 9111860 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7913 (Electronic) Linking ISSN: 09248579 NLM ISO Abbreviation: Int J Antimicrob Agents Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Amsterdam : Elsevier Science Publishers, c1991-
مواضيع طبية MeSH: Cryptococcus neoformans*/drug effects , Cryptococcus neoformans*/genetics , Antifungal Agents*/pharmacology , Proteomics* , Fenbendazole*/pharmacology , Protein Kinases*/metabolism , Protein Kinases*/genetics , Cryptococcosis*/drug therapy , Cryptococcosis*/microbiology, Animals ; Mice ; Amphotericin B/pharmacology ; Fungal Proteins/genetics ; Fungal Proteins/metabolism ; Microbial Sensitivity Tests ; Disease Models, Animal ; Drug Resistance, Fungal/genetics
مستخلص: Cryptococcus neoformans is responsible for over 100 000 deaths annually, and the treatment of this fungal disease is expensive and not consistently effective. Unveiling new therapeutic avenues is crucial. Previous studies have suggested that the anthelmintic drug fenbendazole is an affordable and nontoxic candidate to combat cryptococcosis. However, its mechanism of anticryptococcal activity has been only superficially investigated. In this study, we examined the global cellular response of C. neoformans to fenbendazole using a proteomic approach (data are available via ProteomeXchange with identifier PXD047041). Fenbendazole treatment mostly impacted the abundance of proteins related to metabolic pathways, RNA processing, and intracellular traffic. Protein kinases, in particular, were significantly affected by fenbendazole treatment. Experimental validation of the proteomics data using a collection of C. neoformans mutants led to the identification of critical roles of five protein kinases in fenbendazole's antifungal activity. In fact, mutants lacking the expression of genes encoding Chk1, Tco2, Tco3, Bub1, and Sch9 kinases demonstrated greater resistance to fenbendazole compared to wild-type cells. In combination with the standard antifungal drug amphotericin B, fenbendazole reduced the cryptococcal burden in mice. These findings not only contribute to the elucidation of fenbendazole's mode of action but also support its use in combination therapy with amphotericin B. In conclusion, our data suggest that fenbendazole holds promise for further development as an anticryptococcal agent.
(Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)
فهرسة مساهمة: Keywords: Antifungal activity; Cryptococcus neoformans; Fenbendazole; Protein kinases; Proteomics
المشرفين على المادة: 0 (Antifungal Agents)
621BVT9M36 (Fenbendazole)
EC 2.7.- (Protein Kinases)
7XU7A7DROE (Amphotericin B)
0 (Fungal Proteins)
تواريخ الأحداث: Date Created: 20240328 Date Completed: 20240430 Latest Revision: 20240430
رمز التحديث: 20240430
DOI: 10.1016/j.ijantimicag.2024.107157
PMID: 38548248
قاعدة البيانات: MEDLINE
الوصف
تدمد:1872-7913
DOI:10.1016/j.ijantimicag.2024.107157