Past, Present, and Future of Antifungal Drug Development

2016 ◽  
pp. 125-167 ◽  
Author(s):  
P. K. Shukla ◽  
Pratiksha Singh ◽  
Ravindra Kumar Yadav ◽  
Smriti Pandey ◽  
Shome S. Bhunia
Keyword(s):  
Drug Development ◽  
Antifungal Drug

Structure-based design of δ-lactones for new antifungal drug development: susceptibility, mechanism of action, and toxicity

2019 ◽  
Vol 64 (4) ◽  
pp. 509-519 ◽  
Author(s):  
Daiane F. Dalla Lana ◽  
Ânderson R. Carvalho ◽  
William Lopes ◽  
Marilene H. Vainstein ◽  
Luciano S. P. Guimarães ◽  
...  
Keyword(s):  
Drug Development ◽  
Mechanism Of Action ◽  
Antifungal Drug

NEW ORIGINAL DRUG ROSEOFUNGIN-AS, OINTMENT 2%

2021 ◽  
pp. 55-64
Author(s):  
А.К. САДАНОВ ◽  
В.Э. БЕРЕЗИН ◽  
И.Р. КУЛМАГАМБЕТОВ ◽  
Л.П. ТРЕНОЖНИКОВА ◽  
А.С. БАЛГИМБАЕВА
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Physicochemical Properties ◽  
Phase I ◽  
Mechanism Of Action ◽  
Chemical Structure ◽  
Antifungal Drug ◽  
Polyene Antibiotic

В статье приводятся сведения о разработке нового отечественного противогрибкового препарата «Розеофунгин-АС, мазь 2%» для наружного применения на основе оригинального природного полиенового антибиотика розеофунгина. Приводятся данные о продуценте антибиотика, процессе его биосинтеза и получения, его физико-химических свойствах и химической структуре, рассматриваются его антифунгальные и антивирусные свойства, механизм его действия, а также основные этапы разработки противогрибкового препарата - доклинические и I, II и III фазы клинических исследований. This paper provides the information on the development of new domestic antifungal drug Roseofungin-AS, ointment 2% for external use based on the original natural polyene antibiotic roseofungin. Data on the antibiotic producer, the process of its biosynthesis and production, its physicochemical properties and chemical structure are presented, its antifungal and antiviral properties, the mechanism of action as well as the main stages of the antifungal drug development including preclinical and phase I, II, III clinical trials are discussed.

scholarly journals Antifungal Drug Development: Targeting the Fungal Sphingolipid Pathway

2020 ◽  
Vol 6 (3) ◽  
pp. 142
Author(s):  
Kyle McEvoy ◽  
Tyler G. Normile ◽  
Maurizio Del Poeta
Keyword(s):  
Drug Resistance ◽  
Drug Development ◽  
Mechanism Of Action ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Antifungal Compounds ◽  
Metabolizing Enzymes ◽  
Progressive Development

Fungal infections are becoming more prevalent and problematic due to the continual rise of immune deficient patients as well as the progressive development of drug resistance towards currently available antifungal drugs. There has been a significant increase in the development of antifungal compounds with a similar mechanism of action of current drugs. In contrast, there has been very little progress in developing compounds inhibiting totally new fungal targets or/and fungal pathways. This review focuses on novel compounds recently discovered to target the fungal sphingolipids and their metabolizing enzymes.

scholarly journals Precise Expression of Afmed15 Is Crucial for Asexual Development, Virulence, and Survival of Aspergillus fumigatus

mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Luyu Guan ◽  
Ruiyang Lu ◽  
Zhengjun Wu ◽  
Guowei Zhong ◽  
Shizhu Zhang
Keyword(s):  
Drug Development ◽  
Aspergillus Fumigatus ◽  
Fungal Pathogens ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Asexual Development ◽  
Fungal Virulence ◽  
Content Type ◽  
Precise Expression

ABSTRACT The rise of drug resistance in fungal pathogens is becoming a serious problem owing to the limited number of antifungal drugs available. Identifying and targeting factors essential for virulence or development unique to fungal pathogens is one approach to develop novel treatments for fungal infections. In this study, we present the identification and functional characterization of a novel developmental regulator in Aspergillus fumigatus, AfMed15, which contained a conserved Med15_fungal domain, as determined by screening of a mutant library that contained more than 2,000 hygromycin-resistant A. fumigatus transformants. Downregulating the expression of Afmed15 abolished the conidiation and decreased the fungal virulence in an insect model. Strikingly, the overexpression of Afmed15 caused fungal death accompanied by intensive autophagy. RNA sequencing of an Afmed15 overexpression strain revealed that altered gene expression patterns were associated with carbon metabolism, energy metabolism, and translation. Interestingly, the addition of metal ions could partially rescue fungal death caused by the overexpression of Afmed15, indicating that disordered ion homeostasis is a potential reason for the fungal death caused by the overexpression of Afmed15. Considering that the precise expression of Afmed15 is crucial for fungal development, virulence, and survival and that no ortholog was found in humans, Afmed15 is an ideal target for antifungal-drug development. IMPORTANCE The identification and characterization of regulators essential for virulence or development constitute one approach for antifungal drug development. In this study, we screened and functionally characterized Afmed15, a novel developmental regulator in A. fumigatus. We demonstrate that the precise transcriptional expression of Afmed15 is crucial for fungal asexual development, virulence, and survival. Downregulating the expression of Afmed15 abolished the conidiation and decreased the fungal virulence in an insect model. In contrast, the overexpression of Afmed15 caused fungal death accompanied by intensive autophagy. Our study provides a foundation for further studies to identify compounds perturbing the expression of Afmed15 that may be used for the prevention of invasive A. fumigatus infections.

scholarly journals TargetingCandida albicansfilamentation for antifungal drug development

Virulence ◽  
2016 ◽  
Vol 8 (2) ◽  
pp. 150-158 ◽  
Author(s):  
Taissa Vila ◽  
Jesus A. Romo ◽  
Christopher G. Pierce ◽  
Stanton F. McHardy ◽  
Stephen P. Saville ◽  
...  
Keyword(s):  
Drug Development ◽  
Antifungal Drug

scholarly journals Spore Germination as a Target for Antifungal Therapeutics

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Sébastien C. Ortiz ◽  
Mingwei Huang ◽  
Christina M. Hull
Keyword(s):  
Drug Development ◽  
Spore Germination ◽  
Fungal Pathogens ◽  
Fungal Spores ◽  
Fungal Spore ◽  
Antifungal Drug ◽  
Term Survival ◽  
Low Toxicity ◽  
Approved Drugs

ABSTRACT Spores are required for long-term survival of many organisms, including most fungi. For the majority of fatal human fungal pathogens, spore germination is the key process required to initiate vegetative growth and ultimately cause disease. Because germination is required for pathogenesis, the process could hold fungus-specific targets for new antifungal drug development. Compounds that inhibit germination could be developed into high-efficacy, low-toxicity drugs for use in the prevention and/or treatment of fungal spore-mediated diseases. To identify drugs with the ability to inhibit pathogenic fungal spore germination, we developed a novel luciferase-based germination assay, using spores of the meningitis-causing yeast Cryptococcus. We screened the L1300 Selleck Library of U.S Food and Drug Administration-approved drugs and identified 27 that inhibit germination. Of these, 22 inhibited both germination and yeast growth, and 21 have not been previously indicated for use in the treatment of fungal diseases. We quantitated the inhibition phenotypes of 10 specific germination/growth inhibitors in detail and tested one drug, the antiparasitic compound pentamidine, in our mouse intranasal model of cryptococcal infection. We discovered that pentamidine was effective at reducing lung fungal burdens when used in either prophylaxis (before infection) or treatment (after establishing an infection). Due to its efficacy in vivo and low intranasal toxicity, pentamidine is a lead candidate for repurposing for broader use as an antigerminant to prevent spore-mediated disease in immunocompromised patients. Not only does pentamidine provide an opportunity for prophylaxis against fungal spores, but it also provides proof of concept for targeting pathogenic spore germination for antifungal drug development.

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