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

Abstract

The frequency of mycoses caused by drug-resistant fungal pathogen <i>Candida albicans</i> 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(5<i>H</i>)-furanone derivatives have demonstrated antimicrobial, antifungal, and antibiofilm activities. In this study, we report the antifungal activity of the 2(5<i>H</i>)-furanone derivative <b>F105</b>, consisting of three pharmacophores, namely chlorinated 2(5<i>H</i>)-furanone, sulfonyl group, and <i>l</i>-menthol moiety. Although exhibiting moderate antifungal activity alone with the minimum inhibitory concentration (MIC) values of 32-256 μg/mL, <b>F105</b> potentiates the activity of fluconazole and terbinafine with fractional inhibitory concentration index (FICI) values of 0.27-0.50. Thus, 16 μg/mL of <b>F105</b> reduced the MICs of these antifungals against fluconazole-resistant <i>C. albicans</i> isolates four-fold, achieving similar values as for the intermediately susceptible phenotype. Confocal laser scanning microscopy revealed that the fluorescent 2(5<i>H</i>)-furanone derivative <b>F145</b> was also able to penetrate through biofilms formed by <i>C. albicans</i>. Indeed, in the presence of <b>F105</b>, even sub-MIC concentrations of both fluconazole and terbinafine led to significant reduction of <i>C. albicans</i> CFUs in the mature biofilm. Thus, <b>F105</b> 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 <i>C. albicans</i> infections.