2011-01-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/655336摘要：近年來帶有超廣效性的β-內醯胺酶的質體之超級細菌傳播已構成全球公共衛生安全問題。這些無抗生素可治的超級細菌在台灣及其它亞洲國家已出現行蹤。超廣效性的β-內醯胺酶可以分解屬於β-內醯胺種類的抗生素如青黴素, 芽孢素, 碳青黴烯類抗生類。超級細菌的傳播危險性在於其超廣效性的β-內醯胺酶的質體已水平轉移至10-40%的腸內菌 (包括大腸桿菌和克雷伯式肺炎桿菌) 而釀成世界各地爆發性的感染。由於超級細菌對抗生素的不敏感, 目前可供醫療界來選擇以抑制細菌生長的藥物日趨減少。可悲的是繼續研發新一代的抗生素卻反而會加速更新品種的超級細菌之突變, 形成一惡性循環。從宿主之觀點來看, 健康腸道可容納每克1011-1012的共生細菌而維持菌叢生態平衡且不引起黏膜發炎, 可見腸道共生細菌之間競爭及黏膜上皮屏障的重要性。正常生理腸道屏障是由緊密連結之上皮細胞構成而將細菌侷限於腸腔內。因此, 了解共生細菌與超級細菌的互動關係, 黏膜上皮屏障的調節機制, 腸道益生菌及抗菌物質對超級細菌的抑制作用, 將有助於發展對超級細菌感染的預防性或治癒性之療法。我們實驗設計將抗藥性的大腸桿菌投予感染小鼠腸道和人類上皮細胞株, 再測試益生菌及抗菌肽的療效。研究目的為 1) 探討共生細菌與超級細菌之間的互動與競爭關係, 以及利用益生菌重整共生菌叢的可能性。 2) 利用動物模式觀察超級細菌是否對腸道黏膜上皮屏障造成傷害而引起細菌入侵和散布, 以及調節上皮屏障之功能以達到抑制細菌轉移的效用。 3) 採用體外細胞培養模式來測試超級細菌感染對上皮細胞存活和發炎性細胞素改變量之影響, 以及探討抗菌肽對超級細菌之抑菌功能。<br> Abstract: The spread of superbugs with plasmid-borne extended-spectrum beta-lactamases (ESBLs) has become a worldwide problem. Emergence of these antibiotic-resistant bacteria such as New Delhi metallo-beta-lactamase (NDM-1) is recently documented in Taiwan and in neighboring countries. ESBLs are enzymes capable of hydrolysing antibiotics of the beta-lactams category (e.g. penicillins, cephalosporins, and carbapenems). One serious problem is that ~10-40% of enterobacteriaceae strains (particularly Escherichia coli and Klebsiella pneumoniae) already contain the ESBL-plasmids that are capable of horizontal transfer between bacterial species, and are responsible for numerous outbreaks of infection.The antibacterial choices for clinicians are increasingly complicated by multi-drug resistance irrespective of the microbial strain. Unfortunately, the development of new antibiotics are actually speeding the evolution and mutation of superbugs in a vicious cycle. From the point of view of the host, the intestine contains over 500 species of commensal microbes estimated at 1011 to 1012 bacteria per gram of colonic content and normally achieve an eco-balance without overgrowth of particular bacterial strains. Therefore, the understanding of host protective mechanism, such as the competitive interaction between superbug and commensal bacteria, and the intestinal barrier functions may shed light to the development of new therapeutic interventions to combat the superbug issues. Intestinal barrier is composed of tightly linked epithelial cells that confine the bacteria in the luminal space. Potential application of probiotics and natural-derived antimicrobial peptides will limit overgrowth and prevent dissemination of superbugs.We plan to use antibiotic-resistant E. coli to orally gavage and expose mouse intestines and human intestinal epithelial cells for infection, and test the effect of probiotics and antimicrobial peptides for treatment. The aim is to investigate 1) Interaction between antibiotic-resistant superbugs and commensal bacteria, and the possibility of restoring the comensal flora pattern by administering probiotics. 2) Modulation of superbug on the invasiveness of commensal bacteria and the regulatory mechanism of intestinal barrier functions that prevents the dissemination of superbug in animal models. 3) Changes in cell death and inflammatory cytokine levels in intestinal epithelial cells after surpebug infection and the effect of antimicrobial peptides using in vitro cell cultures.超級細菌腸道共生細菌上皮屏障細胞凋亡細菌入侵superbugenteric commensalsepithelial barriercell apoptosisbacterial translocation