Meropenem Prodrugs for XDR-TB

描述（由申请人提供）：结核分枝杆菌是全球细菌感染性疾病死亡的主要原因。耐药菌株（MDR和XDR-TB）是一个新出现的问题，可能在美国导致重大问题，因为超过一半的病例是在外国出生的人。最近，碳青霉烯、美罗培南和克拉维辛的组合显示出体外抗广泛耐药结核菌株的活性，并且对非复制型杆菌有效。美罗培南只有一个小时的半衰期，只能通过注射给药。本申请的目的是合成口服生物可利用的美罗培南前药。已经设计了三种前药策略：1）制备无毒的酰氧基羰基氧基酯（辛二酰酯，辛二酰前药）2）合成戊酰酯或二肽酯，其被肠二肽转运蛋白PepT 1吸收，和3）制备同时释放美罗培南和克拉维汀的二价前药。前药也可用于口服转换治疗由微生物如假单胞菌或不动杆菌引起的严重革兰氏阴性菌感染。前药将在体外和豚鼠体内进行评价。将进行代谢稳定性和Caco-2渗透性研究，以确保充分释放和吸收。在静脉注射美罗培南和口服前药后，将在交叉研究中确定五种候选前药的生物利用度。最后，对于最佳前药，将在口服给药后与静脉内美罗培南输注相比评价美罗培南对肺和脾的渗透。疗效研究将在BSL-3实验室的TB豚鼠模型中进行。 公共卫生相关性：结核病是世界上任何传染性病原体导致死亡的主要原因（全世界每年约200万人）。最近，青霉素类似物美罗培南加上一种分解美罗培南的酶抑制剂（克拉维酸）的组合被证明对极端耐药结核病（XDR-TB）的临床分离株有活性。然而，美罗培南只能通过注射给药，在体内的半衰期很短，只有一个小时。该赠款的目标是制造一些类似物（前药），这些类似物将被口服吸收，并可用于治疗广泛耐药结核病或在医院使用，当患者需要在美罗培南静脉治疗后转为口服治疗时。

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis is the leading cause of bacterial infectious disease deaths worldwide. Drug-resistant strains (MDR and XDR-TB) are an emerging problem and could lead to significant issues in the US because over half of the cases are in foreign born persons. Recently, the combination of the carbapenem, meropenem, and clavulanate was shown to be active against XDR-TB strains in vitro and importantly effective against nonreplicating bacilli. Meropenem only has a one-hour half-life and is administered only by injection. The objectives of this application are to synthesize prodrugs of meropenem that are orally bioavailable. Three prodrug strategies have been designed 1) Make a non-toxic acyloxycarbonyloxy esters (proxetil, suberolyl prodrugs) 2) Synthesize valeryl or dipeptidyl esters that are taken up by PepT1, an intestinal dipeptide transporter and 3) Prepare a bivalent prodrug that releases meropenem and clavulanate simultaneously. The prodrugs could also be used for oral switch therapy for serious Gram-negative infections caused by organisms such as Pseudomonas or Acinetobacter. Prodrugs will be evaluated both in vitro and also in vivo in guinea pigs. Metabolic stability and Caco-2 permeability studies will be done to insure adequate release and uptake. Bioavailability of five candidate prodrugs will be determined in a crossover study after administration of intravenous meropenem and oral prodrugs. Finally, for the best prodrug, meropenem penetration into lung and spleen will be evaluated after oral dosing compared to an intravenous meropenem infusion. Efficacy studies will be conducted in a BSL-3 laboratory in the guinea pig model of TB. PUBLIC HEALTH RELEVANCE: Tuberculosis is the leading cause of deaths due to any infectious agent in the world (~2 million per year worldwide). Recently the combination of a penicillin analog, meropenem, plus an inhibitor of an enzyme that breaks meropenem down (clavulanic acid) was shown to be active against clinical isolates of extremely drug-resistant tuberculosis (XDR-TB). However, meropenem is given only by injection and has a short one-hour half-life in the body. The goal of this grant is to make some analogs (prodrugs) that will be absorbed orally and that can be used to treat XDR-TB or for use in hospitals when patients need to switch to oral therapy after intravenous treatment with meropenem.