In Vitro Confirmation of Siramesine as a Novel Antifungal Agent with In Silico Lead Proposals of Structurally Related Antifungals

Vlainić, Josipa; Jović, Ozren; Kosalec, Ivan; Vugrek, Oliver; Čož-Rakovac, Rozelindra; Šmuc, Tomislav (2021) In Vitro Confirmation of Siramesine as a Novel Antifungal Agent with In Silico Lead Proposals of Structurally Related Antifungals. Molecules, 26 . pp. 3504-3520. ISSN 1420-3049

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Abstract

The limited number of medicinal products available to treat of fungal infections makes control of fungal pathogens problematic, especially since the number of fungal resistance incidents increases. Given the high costs and slow development of new antifungal treatment options, repurposing of already known compounds is one of the proposed strategies. The objective of this study was to perform in vitro experimental tests of already identified lead compounds in our previous in silico drug repurposing study, which had been conducted on the known Drugbank database using a seven-step procedure which includes machine learning and molecular docking. This study identifies siramesine as a novel antifungal agent. This novel indication was confirmed through in vitro testing using several yeast species and one mold. The results showed susceptibility of Candida species to siramesine with MIC at concentration 12.5 g/mL, whereas other candidates had no antifungal activity. Siramesine was also effective against in vitro biofilm formation and already formed biofilm was reduced following 24 h treatment with a MBEC range of 50–62.5 g/mL. Siramesine is involved in modulation of ergosterol biosynthesis in vitro, which indicates it is a potential target for its antifungal activity. This implicates the possibility of siramesine repurposing, especially since there are already published data about nontoxicity. Following our in vitro results, we provide additional in depth in silico analysis of siramesine and compounds structurally similar to siramesine, providing an extended lead set for further preclinical and clinical investigation, which is needed to clearly define molecular targets and to elucidate its in vivo effectiveness as well.

Item Type:	Article
Uncontrolled Keywords:	siramesine ; antifungal activity ; Candida albicans ; in vitro cell experiments ; ergosterol ; molecular docking ; QSAR ; Erg2 ; pKi prediction
Subjects:	NATURAL SCIENCES > Biology
Divisions:	Division of Electronics Division of Materials Chemistry Division of Molecular Medicine
Depositing User:	Josipa Vlainić
Date Deposited:	30 Dec 2021 12:57
URI:	http://fulir.irb.hr/id/eprint/6843
DOI:	10.3390/molecules26123504

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