title: Susceptibility of Candida albicans to new synthetic sulfone derivatives.
abstract: The influence of halogenated methyl sulfones, i.e. bromodichloromethyl-4-chloro-3-nitrophenyl sulfone (named halogenated methyl sulfone 1), dichloromethyl-4-chloro-3-nitrophenyl sulfone (halogenated methyl sulfone 2), and chlorodibromomethyl-4-hydrazino-3-nitrophenyl sulfone (halogenated methyl sulfone 3), on cell growth inhibition, aspartic protease gene (SAP4-6) expression, adhesion to epithelium, and filamentation was investigated. Antifungal susceptibility of the halogenated methyl sulfones was determined with the M27-A3 protocol in the range of 16-0.0313 µg/mL. Adherence to Caco-2 cells was performed in 24-well plates; relative quantification was normalized against ACT1 in cells after 18 h of growth in YEPD and on Caco-2 cells. SAP4-6 expression was analyzed using RT-PCR. Structure-activity relationship studies suggested that halogenated methyl sulfone 1 containing bromodichloromethyl or dichloromethyl function at C-4 (halogenated methyl sulfone 2) of the phenyl ring showed the best activity (100% cell inhibition at 0.5 µg/mL), while hydrazine at C-1 (halogenated methyl sulfone 3) reduced the sulfone potential (100% = 4 µg/mL). SAP4-6 were up- or down-regulated depending on the strains' genetic background and the substitutions on the phenyl ring. Halogenated methyl sulfone 2 repressed germination and affected adherence to epithelium (P ≤ 0.05). The tested halogenated methyl sulfones interfered with the adhesion of Candida albicans cells to the epithelial tissues, without affecting their viability after 90 min of incubation. The mode of action of the halogenated methyl sulfones was attributed to the reduced virulence of C. albicans. SAP5 and SAP6 contribute to halogenated methyl sulfones resistance. Thus, halogenated methyl sulfones can inhibit biofilm formation due to their interference with adherence and with the yeast-to-hyphae transition.
authors: National Institute of Public Health - National Institute of Hygiene, Warsaw, Poland.
authors: Monika
authors: M
authors: Staniszewska
authors: Małgorzata
authors: M
authors: Bondaryk
authors: Zbigniew
authors: Z
authors: Ochal
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D018938:Caco-2 Cells; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity; D002448:Cell Adhesion / Q000187:drug effects; D015195:Drug Design; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D054884:Host-Pathogen Interactions; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D012331:RNA, Fungal / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology*; D014774:Virulence
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D012331:RNA, Fungal; D012333:RNA, Messenger; D013450:Sulfones; D016282:Aspartic Acid Endopeptidases; C086392:SAP4 protein, Candida albicans; C090755:SAP5 protein, Candida albicans; C582621:SAP6 protein, Candida albicans
keywords: Adhesion; Aspartic protease genes SAP4-6; Candida albicans; Morphogenesis; Sulfone derivatives