Clinical Microbiology and Infectious Diseases, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa.
University of Jeddah, College of Science, Department of Chemistry, Jeddah 21589, Saudi Arabia.
J Adv Res. 2020 Nov 10;29:121-135. doi: 10.1016/j.jare.2020.11.002. eCollection 2021 Mar.
The fungal pathogen , 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. 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 isolates. 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 after exposure to piperidine derivatives using different kits. Additionally, fluorescence microscopy was done to check the effect of test compound on membrane integrity and related apoptotic assays were performed to confirm cellular apoptosis using different apoptosis markers. 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 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. Present study suggests that the novel derivatives (pta1-pta3) induce apoptotic cell death and cell cycle arrest in and could be potential candidates against infections.
真菌病原体 是对公共健康的严重威胁，与血液感染有关，尤其是在患有严重医疗问题的患者中，死亡率很高。由于这种病原体通常对所有可用类别的抗真菌药物都具有抗性，因此人们一直需要具有新的抗真菌作用机制的新型抗真菌药物。因此，在这项研究中，我们合成了六个新型哌啶基 1,2,3-三唑基乙酰胺衍生物（pta1-pta6），并测试了它们对临床分离株的抗真菌活性和作用机制。根据 CLSI 推荐的指南，进行抗真菌药敏试验以估计哌啶衍生物的 MIC 值。使用不同的试剂盒，通过 MUSE 细胞分析仪检查哌啶衍生物暴露后细胞活力和细胞周期停滞。此外，荧光显微镜用于检查测试化合物对 细胞膜完整性的影响，并使用不同的凋亡标志物进行相关的凋亡测定以确认细胞凋亡。在这六个衍生物中；pta1、pta2 和 pta3 表现出最高的活性，MIC 值为 0.24 至 0.97 μg/mL，MFC 范围为 0.97 至 3.9 μg/mL。通过细胞计数和活力测定证实了这些化合物的杀菌作用。在亚抑制和抑制浓度下暴露于测试化合物会导致 质膜破裂。进一步的深入研究表明，这些衍生物能够诱导 细胞凋亡和 S 期细胞周期停滞。此外，这些化合物表现出较低的毒性特征。本研究表明，新型衍生物（pta1-pta3）可诱导 细胞发生凋亡性细胞死亡和 S 期细胞周期停滞，可能是针对 感染的潜在候选药物。
