2019-08-012024-05-15https://scholars.lib.ntu.edu.tw/handle/123456789/665971摘要：念珠菌是造成院內感染的重要致病菌，臨床上念珠菌抗藥性問題也益發嚴重。目前所使用的抗真菌藥物種類不多再加上有些抗真菌藥物副作用強，因此開發新作用機制的抗菌藥物有其必要與急迫性。粒線體在真核細胞內的生理與代謝反應扮演重要角色，例如念珠菌致病因子的調控，包括菌絲生成、生物膜形成、適應各種環境壓力、細胞壁的合成和組成成分改變、與先天免疫細胞的交互作用和抗藥性能力等。事實上目前一些研究也指出粒線體可能是一個良好的抗真菌藥物標的。 在我們先前利用不同標準念珠菌屬及來自臨床檢體中所篩選出來的抗藥性念珠菌屬的研究中，已確認能造成粒線體失能的BMVC-12C-P小分子化合物不但對念珠菌具毒殺效果，且能夠抑制存活白色念珠菌的菌絲生成能力。這一個研究計畫在於探討BMVC-12C-P作為抗真菌藥物的作用機轉，並針對其特性設計一個藥物遞送系統來檢視其在生物膜及活體的殺菌功效，最終目的希望能將這一個小分子化合物開發成為一個有藥效的先導藥物。為達此目的，我們將自三個方向來進行本研究計畫。第一、確認粒線體為BMVC-12C-P影響白色念珠菌生長及分化的主要作用胞器；第二、釐清BMVC-12C-P所引發生物效應的作用機轉；第三、針對後續可能適應症來發展BMVC-12C-P的藥物遞送系統。 <br> Abstract: Fungal infections, particularly Candida species, have increased worldwide and cause high morbidity and mortality rates. Presently, azole antifungal agents are the major drugs used for the treating fungal infections. However, severe side effects and the increase in the drug-resistant isolates of Candida species has been found. Therefore, development of a new antifungal drug with lower cytotoxicity to normal cell is urgently needed. Previously, we have found that BMVC-12C-P (3,6-bis (1-methyl-4-vinylpyridinium iodide)-9-(1-(1-methyl-piperidinium iodide) dodecyl) carbazole) has low toxicity toward normal mammalian cells but showed significant antifungal activity against wild-type as well as drug-resistant strains of Candida species. Further studies showed that the fungicidal activity of BMVC-12C-P relates to mitochondrial dysfunction. In this research proposal, we intent to explore the molecular mechanisms involved in BMVC-12C-P mediated mitochondrial dysfunction, which leads to cell death and the suppression of morphogenetic switching, mainly hyphal growth. To this end, we will conduct this research proposal in three directions. First, to confirm that mitochondria are the main acting organelles of BMVC-12C-P in affecting the growth and differentiation of Candida albicans. Second, to clarify the mechanism of action of the biological consequences, such as cell death and retardation of hyphal growth induced by BMVC-12C-P. Finally, a drug delivery system will be developed for the subsequent possible indications.白色念珠菌粒線體菌絲抗真菌藥物Candida albicansmitochondriahyphalantifungal drug