Increasing Susceptibility of Drug-Resistant Candida albicans to Fluconazole and Terbinafine by 2(5H)-Furanone Derivative.

Irshad S Sharafutdinov,Almira R Kurbangalieva,Georgii D Ozhegov,Mikhail I Bogachev,Airat R Kayumov,Alina E Sabirova,Valentina V Novikova,Alsu M Khabibrakhmanova,Svetlana A Lisovskaya

doi:10.3390/molecules25030642

Abstract

The frequency of mycoses caused by drug-resistant fungal pathogen Candida albicans has increased drastically over the last two decades. The spread of drug-resistant strains, along with the limitations of currently available antifungals, complicates the management of fungal infections, thereby representing great challenges for clinical healthcare. Among various antimicrobial pharmacophores, 2(5H)-furanone derivatives have demonstrated antimicrobial, antifungal, and antibiofilm activities. In this study, we report the antifungal activity of the 2(5H)-furanone derivative F105, consisting of three pharmacophores, namely chlorinated 2(5H)-furanone, sulfonyl group, and l-menthol moiety. Although exhibiting moderate antifungal activity alone with the minimum inhibitory concentration (MIC) values of 32–256 μg/mL, F105 potentiates the activity of fluconazole and terbinafine with fractional inhibitory concentration index (FICI) values of 0.27–0.50. Thus, 16 μg/mL of F105 reduced the MICs of these antifungals against fluconazole-resistant C. albicans isolates four-fold, achieving similar values as for the intermediately susceptible phenotype. Confocal laser scanning microscopy revealed that the fluorescent 2(5H)-furanone derivative F145 was also able to penetrate through biofilms formed by C. albicans. Indeed, in the presence of F105, even sub-MIC concentrations of both fluconazole and terbinafine led to significant reduction of C. albicans CFUs in the mature biofilm. Thus, F105 appears to be a promising candidate for the development of novel antifungal agents as well as enhancers of current antifungal agents, particularly for the treatment of drug-resistant C. albicans infections.

Highlights

Candida albicans, commonly found in human microbiota, can under certain conditions cause a range of opportunistic diseases, especially in immunocompromised patients [1]
The antimycotic activity of 2(5H)-furanone derivative F105 carrying sulfonyl and l-menthol moieties was evaluated using a range of C. albicans clinical isolates (n = 26) and C. albicans NCTC® 885-653 moieties was evaluated using a range of C. albicans clinical isolates (n = 26) and C. albicans from the National Collection of Type Cultures (Perm, Russia) (Table 1)
All clinical resistant to fluconazole (MIC ≥ 8 μg/mL according to M27-S4 guidelines prepared by the Clinical isolates were resistant to fluconazole (MIC ≥ 8 μg/mL according to M27-S4 guidelines prepared by Laboratory Standards Institute (CLSI)), and moderately susceptible to terbinafine and nystatine [9,27]

Summary

Introduction

Commonly found in human microbiota, can under certain conditions cause a range of opportunistic diseases, especially in immunocompromised patients [1]. The overgrowth of C. albicans often leads to chronic infections of mouth [2], skin [3], or genitourinary tract [4] known as candidiasis. Various treatment options for C. albicans infections are available to date, ranging from topical antifungal agents chlorohexidine and nystatin [5] to systemic drugs such as terbinafine, fluconazole, and novel echinocandins [6]. Rising resistance of Candida to antifungals requires the development of new drugs [7,8]. A triazole antifungal agent fluconazole, commonly prescribed for Candida infections, is predisposed to causing the development acquired resistance since it exhibits only fungistatic activity [11]

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