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 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.
The authors are grateful to the Center of Microscopy and Microanalysis-UFRGS for the SEM.
Daiane F. Dalla Lana, Ânderson R. Carvalho, and William Lopes conceived, planned, and carried out the experiments. Marcus M. Sá, Theo V. C. Russo, and Gustavo P. Silveira synthesized and characterized the samples. Marilene H. Vainstein, Luciano S. P. Guimarães, Mário L. Teixeira, Luis F.S. de Oliveira, and Michel M. Machado assisted in the toxicological and statistical analyses and in obtaining the images from scanning electron microscopy. Alexandre M. Fuentefria and Saulo F. de Andrade contributed to the interpretation of the results and supervision of all the work. Daiane F. Dalla Lana took the lead in writing the manuscript and performed the general research. All authors provided critical feedback and helped shape the research, analysis, and manuscript.
This work was funded by the Brazilian agencies Coordination for the Improvement of Higher Education Personnel (CAPES, Finance Code 001), National Council for Scientific and Technological Development (CNPq), and Foundation for Research Support of the State of Rio Grande do Sul (FAPERGS; Edital PRONUPEQ 2016). G. P. Silveira received financial support from CAPES-UdelaR bilateral collaboration (grant no. 049-2013). A. M. Fuentefria, M. Apel, and M. M. Sá received PQ fellowships from CNPq.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
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