title: New synthetic sulfone derivatives inhibit growth, adhesion and the leucine arylamidase APE2 gene expression of Candida albicans in vitro.
abstract: The successful preventing and effective treatment of invasive Candida albicans infections required research focused on synthesis of new classes of agents and antifungal activity studies. Bromodichloromethyl-4-chloro-3-nitrophenyl sulfone (named compound 6); dichloromethyl-4-chloro-3-nitrophenyl sulfone (named 7); and chlorodibromomethyl-4-hydrazino-3-nitrophenyl sulfone (named 11) on inhibition of planktonic cells' growth, leucine arylamidase APE2 gene expression, and adhesion to epithelial cells were investigated. In vitro anti-Candida activities were determined against wild-types, and the morphogenesis mutants: Δefg1 and Δcph1. MICs of compounds 6, 7 and 11 (concentrated at 0.25-16μg/ml) were determined using the Clinical and Laboratory Standards Institute Broth Microdilution Method (M27-A3 Document). APE2 expression was analyzed using RT-PCR; relative quantification was normalized against ACT1 in cells growth in YEPD and on Caco-2 cell line. Adherence assay of C. albicans to Caco-2 was performed in 24-well-plate. The structure activity relationship suggested that sulfone containing hydrazine function at C-1 (compound 11) showed higher antifungal activity (cell inhibition%=100 at 1-16μg/ml) than the remaining sulfones with chlorine at C-1. Δcph1/Δefg1 was highly sensitive to compound 11, while the sensitivity was reduced in Δcph1/Δefg1::EFG1 (%=100 at 16-fold higher concentration). Compound 11 significantly affected adherence to epithelium (P ⩽0.05) and hyphae formation. The APE2 up-regulation plays role in sulfones' resistance on MAP kinase pathway. Either CPH1 or EFG1 play a role in the resistance mechanism in sulfones. The strain-dependent phenomenon is a factor in the sulfone resistance mechanism. Sulfones' mode of action was attributed to reduced virulence arsenal in terms of adhesiveness and pathogenic potential related to the APE2 expression and morphogenesis.
authors.affiliation: Independent Laboratory of Streptomyces and Fungi Imperfecti, National Institute of Public Health-National Institute of Hygiene, Chocimska 24, 00-791 Warsaw, Poland. Electronic address: mstaniszewska@pzh.gov.pl.
authors.forename: Monika
authors.initials: M
authors.lastname: Staniszewska
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.affiliation: Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Ochal
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018938:Caco-2 Cells; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects*; D006801:Humans; D006834:Hydrazines / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D006834:Hydrazines; D013450:Sulfones; C029424:hydrazine
keywords: APE2; Adhesion; Anti-virulence agents; Candida albicans; Morphogenesis; Sulfone derivatives