2016-05-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/659812摘要：多重抗藥性金黃色葡萄球菌於全球的陸續出現，除增加治療的困難外，亦升高了受感染者的死亡 率。在此同時，由於在發現新藥物結構及機制上遇到困難，很少有新一類的抗菌藥物被引入臨床 使用。因此，這一迫切且尚未被滿足的需求，已成為一個亟需藥廠和學界共同努力的藥物研發目 標。在先前的研究中，我們發現一個酪氨酸激酶抑製劑sorafcnib，具有抗金黃色葡萄球菌的抗菌 活性。據此，我們以sorafcnib結構為基礎，開發出對致病性葡萄球菌，多重抗藥性金黃色葡萄球 菌(含100株臨床分離株)及其它革蘭氏陽性致病菌，皆具高度抑菌活性的藥物SC5005。動物實驗 亦證實，以腹腔注射方式給予受MRSA感染的小鼠10 mg/kg的SC5005，可大幅增加其存活率。 後續機制研究指出，SC5005的殺菌活性是經由破壞細胞膜完整性。因為其獨特作用機制，即使 在以SC5005連續處理金黃色葡萄球菌200天，細菌亦無法產生抗藥性，且細菌對SC5005的自然 抗藥機率為<1/1(V°。因此，SC5005為一個極具開發潛力之抗金黃色葡萄球菌的前驅藥物。在此， 我們提出一個跨機構(台灣大學與陽明大學)合作計畫，去進一步優化SC5005的結構，以增強其殺 菌能力與臨床可用性。我們預計從超過100個新生成的結構衍生物中，篩選在體外與體內皆有較 佳殺菌活性的候選藥物，以進一步朝臨床前期試驗前進。<br> Abstract: The past few decades have witnessed the global emergency of MRSA, which has rendered thetreatment of Staphylococcus aureus infection difficult, leading to a higher mortality in patients.Unfortunately, very few novel classes of antibacterial drugs have been introduced, in part, due todifficulties in identifying new active structure and action mechanism for drug discovery. This discoveryvoid created an unmet need for innovative drug discovery programs at pharmaceutical companies andacademic institutions alike. Previous, based on our finding that the tyrosine protein kinase inhibitorsorafenib exhibited a unique, off-target ability to kill S. aureus, we developed a novel class ofanti-MRSA agents, as represented by the lead compound SC5005, with high potency against a panel ofStaphylococcus pathogens, different strains of MRSA, including 100 clinical isolates from NTUH, andother Gram-positive pathogenic bacteria. Moreover, intraperitoneal administration of compoundSC5005 at 10 mg/kg significantly improved the survival of MRSA infected C57BL/6 mice. Subsequentmechanism study indicated that SC5005 kills MRSAs via disrupting membrane integrity. Due to itsunique action mechanism, no resistance in S. aureus was identified after a 200-day exposure tosub-lethal concentration of SC5005, and the spontaneous resistant rate is below 1/1010. Thus, SC5005represents a promising lead compound for the development of a novel anti-MRSA agent. Here, weproposed a bi-institutional collaboration (National Taiwan University, and National Yang-MingUniversity) to further optimize the structure of SC5005 to enhance its antibacterial activity as well asclinical feasibility. We aim to synthesize over 100 structure derivatives of SC5005 and expect toidentified a potential candidate with better in vitro and in vivo activities for subsequent preclinicalstudies.