title: Sulfone derivatives reduce growth, adhesion and aspartic protease SAP2 gene expression.
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.
authors.affiliation: Independent Laboratory of Streptomyces and Fungi Imperfecti, National Institute of Public Health, National Institute of Hygiene, Chocimska 24, 00-791, Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Bondaryk
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Ochal
authors.forename: Monika
authors.initials: M
authors.lastname: Staniszewska
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018938:Caco-2 Cells; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects*; D004847:Epithelial Cells / Q000382:microbiology; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D013696:Temperature; D013997:Time Factors
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D013450:Sulfones; D016282:Aspartic Acid Endopeptidases; C090753:SAP2 protein, Candida