Meropenem Prodrugs for XDR-TB

描述（由申请人提供）：结核分枝杆菌是全球细菌性传染病死亡的主要原因。耐药菌株（MDR和XDR-TB）是一个新出现的问题，并且可能在美国导致重大问题，因为超过一半的病例发生在外国出生的人身上。最近，碳青霉烯、美罗培南和克拉维酸酯联合使用在体外对广泛耐药结核菌株有活性，对非复制性杆菌有重要作用。美罗培南只有一小时的半衰期，只能通过注射给药。本申请的目的是合成口服生物利用的美罗培南前药。设计了三种前药策略：(1)制备无毒的酰基羰基氧基酯（proxetil， suberolyl前药）；(2)合成由肠道二肽转运体PepT1吸收的戊酰或二肽基酯；(3)制备同时释放美罗培南和克拉维酸的二价前药。前药也可用于由假单胞菌或不动杆菌等生物引起的严重革兰氏阴性感染的口服转换治疗。前药将在豚鼠体内和体外进行评估。将进行代谢稳定性和Caco-2渗透性研究，以确保充分的释放和吸收。五种候选前药的生物利用度将在静脉注射美罗培南和口服前药后的交叉研究中确定。最后，对于最佳前药，口服美罗培南与静脉输注美罗培南相比，美罗培南对肺和脾脏的渗透将被评估。疗效研究将在结核病豚鼠模型的BSL-3实验室进行。

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.