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

Dermatophytes are the etiological agents of cutaneous mycoses, including the prevalent nail infections and athlete’s foot. Candida spp. are opportunistic and emerging pathogens, causing superficial to deeper infections related to high mortality rates. As a consequence of prolonged application of ant...

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Bibliographic Details
Published in:Folia microbiologica 2019-07, Vol.64 (4), p.509-519
Main Authors: Dalla Lana, Daiane F., Carvalho, Ânderson R., Lopes, William, Vainstein, Marilene H., Guimarães, Luciano S. P., Teixeira, Mário L., de Oliveira, Luis F. S., Machado, Michel M., de Andrade, Saulo F., Sá, Marcus M., Russo, Theo V. C., Silveira, Gustavo P., Fuentefria, Alexandre M.
Format: Article
Language:English
Subjects:
Antifungal activity
Applied Microbiology
Biological activity
Biomedical and Life Sciences
Candida
Cell walls
Chorioallantoic membrane
Drug development
Drug resistance
Electron microscopy
Environmental Engineering/Biotechnology
Etiology
Fungi
Fungicides
Genotoxicity
Immunology
Lactones
Leukocytes
Life Sciences
Microbiology
Minimum inhibitory concentration
Opportunist infection
Original Article
Structural damage
Toxicity
Viability
Yeasts
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Summary:Dermatophytes are the etiological agents of cutaneous mycoses, including the prevalent nail infections and athlete’s foot. Candida spp. are opportunistic and emerging pathogens, causing superficial to deeper infections related to high mortality rates. As a consequence of prolonged application of antifungal drugs, the treatment failures combined with multidrug-resistance have become a serious problem in clinical practice . Therefore, novel alternative antifungals are required urgently. δ-Lactones have attracted great interest owing to their wide range of biological activity. This article describes the antifungal activity of synthetic δ-lactones against yeasts of the genus Candida spp. and dermatophytes (through the broth microdilution method), discusses the pathways by which the compounds exert this action (toward the fungal cell wall and/or membrane), and evaluates the toxicity to human leukocytes and chorioallantoic membrane (by the hen’s egg test-chorioallantoic membrane). Two of the compounds in the series presented broader spectrum of antifungal activity, including against resistant fungal species. The mechanism of action was related to damage in the fungal cell wall and membrane, with specific target action dependent on the type of substituent present in the δ-lactone structure. The damage in the fungal cell was corroborated by electron microscopy images, which evidenced lysed and completely altered cells after in vitro treatment with δ-lactones. Toxicity was dose dependent for the viability of human leukocytes, but none of the compounds was mutagenic, genotoxic, or membrane irritant when evaluated at higher concentrations than MIC. In this way, δ-lactones constitute a class with excellent perspectives regarding their potential applications as antifungals.
ISSN:0015-5632
1874-9356
DOI:10.1007/s12223-018-00675-y