2011-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/659802摘要：金黃色葡萄球菌是一重要的革蘭氏陽性致病菌。在臨床上，金黃色葡萄球菌已對多種現今常用的第一線及第二線抗生素產生抗藥性，進而在治療上造成嚴重的問題。因此，開發新型態抗金黃色葡萄球菌的抗菌劑，用於控制多重抗藥性金黃色葡萄球菌所造成的感染，有其迫切的必要性。在試圖尋找具抗金黃色葡萄球菌能力的先導藥物時，我們檢測了數個臨床上使用的非抗生素藥物對葡萄球菌在培養液中生長的影響。在所測試的藥物中，一個專對第二型環氧合酶(cyclooxygenase-2)的抑制劑celecoxib，其展現出對金黃色葡萄球菌、表皮葡萄球菌和抗甲氧西林金黃色葡萄球菌（MRSA）的生長有著明顯的抑制能力。相對的，另一個更強力的第二型環氧合酶抑制劑rofecoxib，卻不具有任何的抗菌活性，此結果指出celecoxib 的抗菌能力和其所具有的第二型環氧合酶抑制能力並不相關。基於這些發現，我們結合我們在藥物化學，藥物開發和對金黃色葡萄球菌耐藥機制研究上的專業技術，以celecoxib 為平台，發展出一個對多重抗藥性的金黃色葡萄球菌具強效力的抑制劑, Cpd-36。在此一計畫中，我們將針對Cpd-36的作用機製、藥物標的和在動物體的療效進行分析及評估，並藉由電腦分子模式的幫助，去設計並篩選出更強更具專一性的抗金黃色葡萄球菌藥物，期望將來能對臨床上多重抗藥性金黃色葡萄球菌的感染提供一個新的解決方案。<br> Abstract: Staphylococcus aureus is an important Gram-positive pathogenic bacterium, which havedeveloped multiple drug resistance and causes serious therapeutic problems in clinical. Thus,development of novel anti-Staphylococcus agents for the control of infections ofmulti-antibiotic resistant S. aureus is needed. With our efforts to find lead anti-Staphylococcusagents, we examined the effects of several clinical used agents on the growth ofStaphylococcus in cation-adjusted Muller Hinton broth. Of the agents screened, thecyclooxygenase-2 inhibitor, celecoxib, exhibits an inhibitory activity against Staphylococcusaureus, Staphylococcus epidermidis and methicillin-resistant Staphylococcus aureus (MRSA)directly in growth medium whereas another more potent cyclooxygenase-2 inhibitor,rofecoxib, didn’t show any antimicrobial activity. The result indicated that the antibacterialactivity of celecoxib is independent of its cyclooxygenase-2 inhibitory ability. Accordingly,we combined our expertise in medicinal chemistry, drug discovery, and mechanism ofantibiotic resistance of S. aureus to develop potent small–molecule agents againstStaphylococcus based on the molecular scaffold of celecoxib. Our efforts lead to theidentification of a potent anti-Staphylococcus agent, Cpd-36. Here, we plan to identify andanalyze the action mechanism, bacterial target protein and in vivo efficacy of Cpd-36. Besides,with the help of computer modeling, we aim to develop a more potent, more specific agent forthe treatment of infection caused by multiple antibiotic resistant Staphylococcus aureus.金黃色葡萄球菌抗MRSA藥劑抗感染藥劑Staphylococcus aureusAnti-MRSA agentsAnti-infection agents