Sulfone derivatives reduce growth, adhesion and aspartic protease SAP2 gene expression

World J Microbiol Biotechnol. 2014 Sep;30(9):2511-21. doi: 10.1007/s11274-014-1676-2. Epub 2014 Jun 1.

Abstract

Fungal virulence factors represent a strategy for the design of new compounds with effective activities against Candida spp. Dichloromethyl-4-chloro-3-nitrophenylsulfone (named Compound 1) and chlorodibromomethyl-4-hydrazino-3-nitrophenylsulfone (Compound 2) versus Candida albicans virulence factors (SAP2 expression and adhesion to Caco-2 cell line) were investigated. Candida albicans SC5314 and its mutants: Δsap9, Δsap10, Δsap9/10 were used. MICs of the Compounds (concentrated at 0.0313-16 µg/ml) were determined using M27-A3. Percentage of cell inhibition was assessed spectrophotometrically (OD405) after 48 h at 35 °C. The SAP2 expression was analyzed with the use of RT-PCR; relative quantification was normalized against ACT1 in cells grown in YEPD and on Caco-2. Adherence assay of C. albicans to Caco-2 was performed in a 24-well-plate. Compound 1 showed higher activity (% = 100 at 4 µg/ml) than Compound 2 (MIC90 = 16 µg/ml). Dichloromethyl at the para position of the phenyl ring exerted anti-Candidal potential. Under Compound 1, SAP2 was down-regulated in all the strains (P ≤ 0.05). Conversely, SAP2 was over-expressed in Δsap9-10 (untreated cells) compared with the wild-type. The Compounds significantly affected adherence to epithelium (P ≤ 0.05). The tested sulfones interfered with the adhesion of C. albicans cells to the epithelial tissues without affecting their viability after 90-min of incubation. The Compounds' mode of action was attributed to the reduced adhesiveness and the lower SAP2 expression. Saps9-10 play a role in C. albicans adhesion and they can be involved in the sulfone resistance mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors
  • Aspartic Acid Endopeptidases / biosynthesis*
  • Caco-2 Cells
  • Candida albicans / drug effects*
  • Candida albicans / growth & development
  • Candida albicans / physiology*
  • Cell Adhesion / drug effects*
  • Epithelial Cells / microbiology
  • Fungal Proteins / antagonists & inhibitors
  • Fungal Proteins / biosynthesis*
  • Gene Expression / drug effects*
  • Gene Expression Profiling
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spectrophotometry
  • Structure-Activity Relationship
  • Sulfones / chemistry
  • Sulfones / pharmacology*
  • Temperature
  • Time Factors

Substances

  • Antifungal Agents
  • Fungal Proteins
  • Sulfones
  • Aspartic Acid Endopeptidases
  • SAP2 protein, Candida