TARGETED THERAPY OF MYCOBACTERIUM AVIUM INFECTIONS

鸟-胞内分枝杆菌复合体（MAC）引起严重的 获得性肺炎患者的播散性细菌感染 免疫缺陷综合征（艾滋病）。 艾滋病患者的MAC感染是 对目前可用的抗分枝杆菌药物具有很大的耐药性。这些 病原体主要位于网状内皮细胞的巨噬细胞中， 系统（RES）。脂质体是磷脂囊泡， 抗生素，并贪婪地采取了由RES。根据以往的 表明几种脂质体包封的药物的上级功效的研究 在米色小鼠和培养的巨噬细胞中对抗MAC感染的抗生素， 该项目的中心假设是， MAC感染的细胞内位点增加了它们的功效， 降低其毒性。 该研究将建立有针对性的 在米色小鼠中的MAC治疗，该疾病的已建立的动物模型。 脂质体的最佳剂量、给药方案和组合- 胶囊化抗生素，包括链霉素、阿米卡星和 氯法齐明，将确定，以达到最大的抗分枝杆菌 在MAC感染的米色小鼠中的作用。 体内治疗效果 包封在脂质体中的有前途的新药，包括环丙沙星， 司帕沙星和克拉霉素。 的影响 脂质体包裹抗生素对人外周血MAC生长的影响 将研究血液单核细胞，以确定脂质体 递送增强了这些抗生素的抗MAC活性， 组合，以及评估其他新的抗分枝杆菌药物。

Mycobacterium avium-intracellulare complex (MAC) causes serious disseminated bacterial infection in patients with the acquired immunodeficiency syndrome (AIDS). MAC infection in AIDS patients is largely resistant to currently available antimycobacterial drugs. These pathogens localize primarily in the macrophages of the reticuloendothelial system (RES). Liposomes are phospholipid vesicles that can encapsulate antibiotics, and are avidly taken up by the RES. Based on previous studies indicating the superior efficacy of several liposome-encapsulated antibiotics against MAC infections in beige mice and cultured macrophages, the central hypothesis of this projects is that targeting antibiotics to the intracellular sites of MAC infection increases their efficacy and reduces their toxicity. The proposed research will establish targeted therapy of MAC in beige mice, an established animal model of this disease. The optimal dose, schedule of administration and combination of liposome- encapsulated antibiotics, including streptomycin, amikacin and clofazimine, will be determined, to achieve maximal antimycobacterial effects in MAC-infected beige mice. The in vivo therapeutic effect of promising new drugs encapsulated in liposomes, including ciprofloxacin, sparfloxacin and clarithromycin, will be investigated. The effect of liposome-encapsulated antibiotics on the growth of MAC in human peripheral blood monocytes will be investigated, to ascertain whether liposomal delivery enhances the anti-MAC activity of these antibiotics and their combinations, as well as to evaluate other new antimycobacterial drugs.