Sulfone derivatives enter the cytoplasm of Candida albicans sessile cells

Monika Staniszewska , Anna Sobiepanek , Małgorzata Gizińska , Eduardo Peña-Cabrera , Ismael J. Arroyo-Córdoba , Michalina Kazek , Łukasz Kuryk , Magdalena Wieczorek , Mirosława Koronkiewicz , Tomasz Kobiela , Zbigniew Ochal

Abstract

Since our study showed that sulfone derivatives’ action mode creates a lesser risk of inducing widespread resistance among Candida spp., we continued verifying sulfones’ antifungal activity using the following newly synthesized derivatives: bromodichloromethy-4-hydrazinyl-3-nitrophenyl sulfone (S1), difluoroiodomethyl-4-hydrazinyl-3-nitrophenyl sulfone (S2), and chlorodifluoromethyl-4-hydrazinyl-3-nitrophenyl sulfone (S3). As the mechanism by which sulfones gain access to the cytoplasm has not been elucidated yet, in order to track S1-3, we coupled their hydrazine group with BODIPY (final S1-3 BODIPY-labelled were named SB1-3). This approach allowed us to follow the vital internalization and endocytic routing of SB1-3, while BODIPY interacts primarily with fungal surfaces, thus confirming that S1-3 and their counterparts SB1-2 behaved as non-typical agents by damaging the cell membrane and wall after being endocytosed (SB1-3 fluorescence visible inside the unlysed sessile cells). Thus greatly decreasing the likelihood of the appearance of strains resistance. Core sulfones S1-3 are a promising alternative not only to treat planktonic C. albicans but also biofilm-embedded cells. In the flow cytometric analysis, the planktonic cell surface was digested by S1-3, which made the externalized PS accessible to AnnexinV binding and PI input (accidental cell death ACD). The occurrence of ACD as well as apoptosis (crescent-shaped nuclei) and anoikis of sessile cells (regulated cell death by 100%-reduction in attachment to epithelium) was assessed through monitoring the AO/PI/HO342 markers. CLSM revealed the invasion of S1-3 and SB1-3 in C. albicans without inducing cell lysis. This was a novel approach in which QCM-D was used for real-time in situ detection of viscoelastic changes in the C. albicans biofilm, and its interaction with S1 as a representative of the sulfones tested. S1 (not toxic in vivo) is a potent fungicidal agent against C. albicans and could be administered to treat invasive candidiasis as a monotherapy or in combination with antifungal agents of reference to treat C. albicans infections.

Author Monika Staniszewska (FC / CDSB)
Monika Staniszewska,,
- Chair of Drug and Cosmetics Biotechnology
, Anna Sobiepanek (FC / CDSB)
Anna Sobiepanek,,
- Chair of Drug and Cosmetics Biotechnology
, Małgorzata Gizińska - [KONDRAT&Partners]
Małgorzata Gizińska,,
-
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, Eduardo Peña-Cabrera - [Universidad de Guanajuato]
Eduardo Peña-Cabrera,,
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, Ismael J. Arroyo-Córdoba - [Universidad de Guanajuato]
Ismael J. Arroyo-Córdoba,,
-
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, Michalina Kazek
Michalina Kazek,,
-
, Łukasz Kuryk - [National Medicines Institute, Warsaw]
Łukasz Kuryk,,
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, Magdalena Wieczorek - [National Medicines Institute, Warsaw]
Magdalena Wieczorek,,
-
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, Mirosława Koronkiewicz (FC)
Mirosława Koronkiewicz,,
- Faculty of Chemistry
, Tomasz Kobiela (FC / CDSB)
Tomasz Kobiela,,
- Chair of Drug and Cosmetics Biotechnology
et al.`
Journal seriesEuropean Journal of Medicinal Chemistry, ISSN 0223-5234, e-ISSN 1768-3254
Issue year2020
Vol191
Pages1-16
Publication size in sheets0.75
Article number112139
Keywords in EnglishBODIPY-Labelled sulfones, Antifungals, Endocytosis, Regulated cell death, Biofilm viscoelastic changes
ASJC Classification2700 General Medicine; 3002 Drug Discovery; 3004 Pharmacology; 1605 Organic Chemistry
DOIDOI:10.1016/j.ejmech.2020.112139
URL https://pubmed.ncbi.nlm.nih.gov/32109777/
Languageen angielski
File
wdpb_publikacje_pliki_plik_publikacja_3954_org.pdf 3.5 MB
Score (nominal)140
Score sourcejournalList
ScoreMinisterial score = 140.0, 01-07-2020, ArticleFromJournal
Publication indicators Scopus Citations = 0; Scopus SNIP (Source Normalised Impact per Paper): 2018 = 1.464; WoS Impact Factor: 2018 = 4.833 (2) - 2018=4.666 (5)
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