Antifungal activity of fibrate-based compounds and substituted pyrroles inhibiting the enzyme 3-hydroxy-methyl-glutaryl-CoA reductase of Candida glabrata (CgHMGR), and decreasing yeast viability and ergosterol synthesis

Madrigal-Aguilar, Damián A.; Gonzalez-Silva, Adilene; Rosales-Acosta, Blanca; Bautista-Crescencio, Celia; Ortiz-Álvarez, Jossué; Escalante, Carlos H.; Sánchez-Navarrete, Jaime; Hernández-Rodríguez, César; Chamorro-Cevallos, Germán; Tamariz, Joaquín; Villa-Tanaca, Lourdes

Due to the emergence of multi-drug resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at alternative molecular targets. The aim of the current study was to evaluate the capacity of synthetic compounds to inhibit the Candida glabrata enzyme denominated 3-hydroxy-methyl-glutaryl-CoA reductase (CgHMGR), and thus affect ergosterol synthesis and yeast viability. One series of synthetic antifungal compounds were analogues to fibrates, a second series had substituted 1,2-dihydroquinolines and the third series included substituted pyrroles. α-asarone-related compounds 1c and 5b with a pyrrolic core were selected as the best antifungal candidates. Both inhibited the growth of fluconazole-resistant C. glabrata 43 and fluconazole-susceptible C. glabrata CBS 138. A yeast growth rescue experiment based on the addition of exogenous ergosterol showed that the compounds act by inhibiting the mevalonate synthesis pathway. A greater recovery of yeast growth occurred for the C. glabrata 43 strain and after the 1c (versus 5b) treatment. Given that the compounds decreased the ergosterol concentration in the yeast strains, they probably target the ergosterol synthesis. According to the docking analysis, the inhibitory effect of the 1c and 5b could possibly be mediated by their interaction with the amino acid residues of the catalytic site of CgHMGR. Since 1c displayed higher binding energy than α-asarone and 5b, it is a good candidate for further research, which should include structural modifications to increase its specificity and potency as well as in vivo studies on its effectiveness at a therapeutic dose. HIGHLIGHTS Fibrate-based and pyrrole-containing compounds were tested as C. glabrata inhibitors. The best inhibitor from fibrate was 1c and from pyrroles was 5b. These agents inhibited C. glabrata growth better than the reference antifungals. They also inhibited ergosterol synthesis by the two C. glabrata strains tested. Experimental