Cellular apoptosis and cell cycle arrest as potential therapeutic targets for eugenol derivatives in Candida auris
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ABSTRACT:
ORGANISM(S): Candida auris
SUBMITTER:
PROVIDER: S-BSST1078 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Candida auris, the youngest Candida species, is known to cause candidiasis and candidemia in humans and has been related to several hospital outbreaks. Moreover, Candida auris infections are largely resistant to the antifungal drugs currently in clinical use, necessitating the development of novel medications and approaches to treat such infections. Following up on our previous studies that demonstrated eugenol tosylate congeners (ETCs) to have antifungal activity, several ETCs (C1-C6) were synthesized to find a lead molecule with the requisite antifungal activity against C. auris. Preliminary tests, including broth microdilution and the MUSE cell viability assay, identified C5 as the most active derivative, with a MIC value of 0.98 g/mL against all strains tested. Cell count and viability assays further validated the fungicidal activity of C5. Apoptotic indicators, such as phosphatidylserine externalization, DNA fragmentation, mitochondrial depolarization, decreased cytochrome c and oxidase activity and cell death confirmed that C5 caused apoptosis in C. auris isolates. The low cytotoxicity of C5 further confirmed the safety of using this derivative in future studies. To support the conclusions drawn in this investigation, additional in vivo experiments demonstrating the antifungal activity of this lead compound in animal models will be needed.
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Project description:Introduction: The fungal pathogen Candida auris, is a serious threat to public health and is associated with bloodstream infections causing high mortality particularly in patients with serious medical problems. As this pathogen is generally resistant to all the available classes of antifungals, there is a constant demand for novel antifungal drugs with new mechanisms of antifungal action. Objective: Therefore, in this study we synthesised six novel piperidine based 1,2,3-triazolylacetamide derivatives (pta1-pta6) and tested their antifungal activity and mechanism of action against clinical C. auris isolates. Methods: Antifungal susceptibility testing was done to estimate MIC values of piperidine derivatives following CLSI recommended guidelines. MUSE Cell Analyzer was used to check cell viability and cell cycle arrest in C. auris after exposure to piperidine derivatives using different kits. Additionally, fluorescence microscopy was done to check the effect of test compound on C. auris membrane integrity and related apoptotic assays were performed to confirm cellular apoptosis using different apoptosis markers. Results: Out of the six derivatives; pta1, pta2 and pta3 showed highest active with MIC values from 0.24 to 0.97 μg/mL and MFC ranging from 0.97 to 3.9 μg/mL. Fungicidal behaviour of these compounds was confirmed by cell count and viability assay. Exposure to test compounds at sub-inhibitory and inhibitory concentrations resulted in disruption of C. auris plasma membrane. Further in-depth studies showed that these derivatives were able to induce apoptosis and cell cycle arrest in S-phase. Furthermore, the compounds demonstrated lower toxicity profile. Conclusion: Present study suggests that the novel derivatives (pta1-pta3) induce apoptotic cell death and cell cycle arrest in C. auris and could be potential candidates against C. auris infections.
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