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Possible role of hydrolytic enzymes (Sap, Kex2) in Candida albicans response to aromatic compounds bearing a sulfone moiety

Abstract

Hydrolytic enzymes e.g., Saps and Kex2 are, due to their role in Candida virulence, considered important targets for new synthetic inhibitors. MICTI and MICPI values indicate that disruption of SAP1-3 significantly increases the resistance of Candida mutants to β-ketosulfone (1). Contrariwise, sap123Δ showed sensitive phenotype to halogenated methylphenyl sulfone (2). Anticandidal potency of 2 differed in the Candida cells of kex2Δ. Sulfone is the most effective agent against the Candida albicans kex2Δ double mutant (MICTI of 0.5 µg mL−1). Up-regulation of KEX2 mediated the resistance of sap4-6Δ towards 2. Both sulfones tested reduced the adhesion of the wild type cells significantly (P ≤ 0.05). Contrariwise, sap123Δ showed significantly enhanced adhesion capability when 1 was used (P ≤ 0.05). Both sulfones had weak fungicidal effect on mature C. albicans biofilms. It was shown that the uptake of IP correlates with the membrane perturbations caused by 1 in the blastoconidial cells. Sulfones were found to disturb the basic developmental phases of biofilm growth: adhesion and morphogenesis. Altered KEX2 levels for 1 can be caused by the compensatory mechanism for the maintenance of cell wall integrity and morphogenesis. KEX2 decreases the antifungal activity of sulfones. Sulfones affecting the crucial virulence factors of Candida can even eliminate these fungal infections.

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Bondaryk, M., Grabowska-Jadach, I., Ochal, Z. et al. Possible role of hydrolytic enzymes (Sap, Kex2) in Candida albicans response to aromatic compounds bearing a sulfone moiety. Chem. Pap. 70, 1336–1350 (2016). https://doi.org/10.1515/chempap-2016-0072

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Keywords

  • antifungal activity
  • Candida albicans
  • Kex2 serine protease
  • secreted aspartyl proteinases (Saps)
  • sulfone derivatives