Meropenem Prodrugs for XDR-TB

描述(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，可能会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的组合被证明在体外对XDR-TB菌株具有活性，并且重要的是对非复制型杆菌有效。美罗培南的半衰期只有一小时，而且只能注射。本申请的目的是合成口服生物利用度的美罗培南前药。设计了三种前药策略：1)合成无毒的酰氧甲氧基酯(丙酸酯、琥珀酰基前药)；2)合成被肠道二肽转运体PepT1摄取的戊酯或二肽酯；3)制备同时释放美罗培南和克拉维酸的二价前药。这些前药还可用于口服替代疗法，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。前药将在体外和在豚鼠体内进行评估。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。5种候选前体药物的生物利用度将在静脉注射美罗培南和口服前体药物后的交叉研究中确定。最后，对于最好的前体药物，美罗培南在口服后对肺和脾的渗透性将与静脉注射美罗培南进行比较。疗效研究将在BSL-3实验室对豚鼠结核病模型进行。

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.