Hybrid Molecules Designed to Enhance Antibiotic Activity

革兰氏阳性菌多重耐药菌株引起的疾病管理存在危机。这项工作将导致开发新的抗生素药物作用于一个新的目标。它既在技术上具有创新性，又与人类健康高度相关。该项目的第一阶段通过同时增加其效力和水溶性来增加革兰氏阳性特异性抗菌药物的治疗潜力。这是通过合成和评估一系列潜在的双功能分子来完成的，这些分子将一种已知的革兰氏阳性特异性DNA聚合酶IIIC抑制剂与另一种已知的与DNA相互作用的分子结合在一起。一种先导化合物已经被确定，该项目的第二阶段将重点进行必要的实验，以宣布该化合物的一种形式为“候选开发”。二期研究计划包括：(1)扩大先导化合物的合成规模；（ii）合成一系列提高水溶性的盐；（iii）在体外对先导化合物的盐和制剂进行评价；（iv）评价有前途的盐和制剂的急性毒性和药代动力学；(v)在革兰氏阳性细菌感染的体内模型中测试有前途的盐和制剂。Microbiotix Inc.及其开发合作伙伴Shire BioChem Inc.将共同进行II期开发候选药物的临床前研究。拟议的商业应用：制药行业正在积极寻求开发能够攻击新目标的抗生素。一种革兰氏阳性特异性抗生素在II期研究中出现，对多种抗生素耐药细菌有效，将具有巨大的治疗和商业潜力，最初可作为治疗住院患者的肠外药物，最终可作为治疗革兰氏阳性感染的一线抗生素。

There is a crisis in the management of diseases caused by multi- antibiotic resistant strains of Gram-positive bacteria. This work will result in the development of new antibiotic drugs acting on a novel target. It is both technologically innovative and highly relevant to human health. Phase I of this project served to increase the therapeutic potential of a Gram-positive specific anti-microbial by simultaneously increasing its potency and water solubility. This was accomplished through the synthesis and evaluation of a series of potentially bifunctional molecules that combine an established Gram-positive specific DNA polymerase IIIC inhibitor with another molecule known to interact with DNA. A lead compound has been identified and Phase II of this program will focus on conducting the experiments necessary to declare a form of this compound as a "candidate for development". The research plan for Phase II combines: (i) scale-up of the synthesis of the lead compound; (ii) synthesis of a series of salts to enhance water solubility; (iii) evaluation of salts and formulations of the lead compound in vitro; (iv) evaluation of acute toxicity and pharmacokinetics of promising salts and formulations; and (v) testing of promising salts and formulations in in vivo models of Gram-positive bacterial infection. Preclinical studies of a defined candidate for development emerging from Phase II will be undertaken by Microbiotix Inc. together with their development partner Shire BioChem Inc. PROPOSED COMMERCIAL APPLICATIONS: The drug industry is aggressively seeking to develop antibiotics that attack novel targets. A Gram-positive specific antibiotic emerging from Phase II effective against multi-antibiotic resistant bacteria would have enormous therapeutic and commercial potential initially as a parenteral drug in the treatment of hospitalized patients and eventually as a first line antibiotic in the treatment of Gram-positive infection.