Hybrid Molecules Designed to Enhance Antibiotic Activity

在由革兰氏阳性菌的多抗生素抗性菌株引起的疾病的管理中存在危机。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。它既具有技术创新性，又与人类健康高度相关。该项目的I期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微生物剂的治疗潜力。这是通过合成和评价一系列潜在的双功能分子来实现的，所述分子将已建立的革兰氏阳性特异性DNA聚合酶IIIC抑制剂与已知与DNA相互作用的另一种分子结合联合收割机。已经确定了一种先导化合物，该计划的第二阶段将侧重于进行必要的实验，以宣布该化合物的一种形式为“候选开发物”。第二阶段的研究计划包括：（一）扩大先导化合物的合成规模;（二）合成一系列盐以提高水溶性;（三）体外评价先导化合物的盐和制剂;（四）评价有希望的盐和制剂的急性毒性和药代动力学;和（v）在革兰氏阳性细菌感染的体内模型中测试有希望的盐和制剂。Microbiotix Inc.将对II期开发中确定的候选药物进行临床前研究。与他们的开发合作伙伴Shire BioChem Inc.拟议的商业应用：制药行业正在积极寻求开发攻击新靶点的抗生素。从II期出现的有效对抗多种抗生素抗性细菌的革兰氏阳性特异性抗生素将具有巨大的治疗和商业潜力，最初作为治疗住院患者的肠胃外药物，并最终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.