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We investigated the role of KEX2 , SAP4-6 , EFG1 , and CPH1 in the virulence of Candida under a novel compound 2-bromo-2-chloro-2-(4-chlorophenylsulfonyl)-1-phenylethanone (Compound 4 ). We examined whether the exposure of C. albicans cells to Compound 4 , non-cytotoxic to mammalian cells, reduces their adhesion to the human epithelium. We next assessed whether the exposure of C. albicans cells to Compound 4 modulates the anti-inflammatory response (IL-10) and induces human macrophages to respond to the Candida cells. There was a marked reduction in the growth of the sap4Δsap5Δsap6Δ mutant cells when incubated with Compound 4 . Under Compound 4 (minimal fungicidal concentration MFC = 0.5-16 µg/mL): (1) wild type strain SC5314 showed a resistant phenotype with down-regulation of the KEX2 expression; (2) the following mutants of C.  albicans : sap4Δ , sap5Δ , sap6Δ , and cph1Δ displayed decreased susceptibility with the paradoxical effect and up-regulation of the KEX2 expression compared to SC5314; (3) the immune recognition of C. albicans by macrophages and (4) the stimulation of IL-10 were not blocked ex vivo . The effect of deleting KEX2 in C. albicans had a minor impact on the direct activation of Compound 4 's antifungal activity . The adhesion of kex2Δ is lower than that of the wild parental strain SC5314, and tends to decrease if grown in the presence of a sub-endpoint concentration of Compound 4 . Our results provide evidence that SAP4-6 play a role as regulators of the anti- Candida resistance to Compound 4 . Compound 4 constitutes a suitable core to be further exploited for lead optimization to develop potent antimycotics.

Role of Virulence Determinants in Candida albicans’ Resistance to Novel 2-bromo-2-chloro-2-(4-chlorophenylsulfonyl)-1-phenylethanone