The Repression of the Candida albicans Growth and Pseudomycelium Formation by Thiomonoterpenoid

Svetlana A. Lisovskaya, Alexander A. Ksenofontov, Pavel S. Bocharov, Elena V. Antina, Galina B. Guseva, Mikhail B. Berezin, Ilmir R. Gilfanov, Roman S. Pavelyev, Matvey O. Sabantsev, Olga V. Ostolopovskaya, Elena Y. Trizna, Svetlana V. Pestova, Svetlana A. Rubtsova, Andrei G. Izmailov, Albert A. Rizvanov, Liliya E. Nikitina, Airat R. Kayumov

Article ID: 8022
Vol 38, Issue 5, 2024
DOI: https://doi.org/10.23812/j.biol.regul.homeost.agents.20243805.291
Received: 20 May 2024; Accepted: 20 May 2024; Available online: 20 May 2024; Issue release: 20 May 2024


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Abstract

Background: In the last decade, the wide spread of the multidrug resistant yeast C. albicans has challenged the development of new approaches to treatment. Among various options, the use of natural and synthetic terpenes as antifungals or enhancers of conventional drugs has been offered in many works. Here we show the effect of the recently synthesized compound isobornane sulfide named KS1 on C. albicans and discuss its potential mechanism of action. Methods: To characterize the impact of the compound on the yeast minimum inhibitory concentration (MIC) determination on clinical isolates, quantitative PCR with reverse transcriptase (qRT-PCR) of efflux genes expression, cytotoxicity determination on eukaryotic cells, bright-field and fluorescent microscopy with KS1 conjugate with BODIPY fluorophore have been used. The in silico prediction of KS1 properties has been performed using the ADMET server, and molecular docking was used for the modeling of KS1 interaction with putative targets. Results: While exhibiting moderate antifungal activity as compared to fluconazole and terbinafine, KS1 has a synergy with both antifungals on resistant clinical isolates while not stimulating the expression of the CDR1 and MDR1 efflux genes. Moreover, KS1 represses hypha formation by C. albicans, reducing the number of germ tubes more than twice compared to the control. It readily penetrates the cell, as shown by confocal microscopy using the created KS1-BODIPY fluorophore conjugate, apparently thereby facilitating the penetration of antifungals into the cell. As judged by the ADMET server, KS1 falls into the category of drug-like compounds and neither inhibits the isoforms of cytochrome P450 nor manifests mutagenicity or carcinogenicity that fits with in vitro data. The molecular docking showed that KS1 has a high affinity for the transcription activator transcription activator (Tec1) protein of C. albicans, responsible for invasion and hypha formation, which fits with the in vitro data. Conclusions: These findings suggest KS1 as promising both a solely antifungal and an enhancer of conventional antimycotics blocking fungal virulence.


Keywords

Candida albicans;synergistic effect;monoterpenoids;molecular docking


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