Piperidine based 1,2,3-triazolylacetamide derivatives induce cell cycle arrest and apoptotic cell death in Candida auris

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 mu g/mL and MFC ranging from 0.97 to 3.9 mu g/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. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University.

Automated summary

The study synthesized six novel piperidine derivatives and tested their antifungal activity and mechanism of action against clinical isolates of C. auris. Among them, pta1, pta2, and pta3 demonstrated the highest activity, lower toxicity, and the ability to induce apoptotic cell death and cell cycle arrest in C. auris.