Development of a Novel Lead Series Against Category A & B Bacterial Pathogens

描述(由申请人提供)：该项目的总体目标是开发一种新型化学类别的广谱治疗剂，双吲哚铅系列，用于对抗革兰氏阴性菌A和B类细菌的生物防御威胁，并在五年拨款结束前提交IND。目前治疗方法的数量和有效性有限，耐药性不断增加，以及对抗生素耐药菌株进行故意改造的可能性，迫切需要开发能够对抗这些生物防御威胁的更有效、更广泛的新抗菌剂。这一新化学系列的化合物表现出广谱的抗菌活性，对革兰氏阴性细菌的生长表现出强大的抑制作用(MIC值为0.3-0.30ug/ml)，包括一些A类和B类药物，如鼠疫耶尔森氏菌、图拉氏方济氏菌、马来伯克霍尔德氏菌和假鼻疽。这些化合物对耐环丙沙星炭疽芽孢杆菌(MIC 0.2-0.4ug/ml)以及其他各种革兰氏阳性和革兰氏阴性细菌也具有活性。它们通过快速杀菌机制发挥作用，在接近MIC值的浓度下，在1-4小时内显示出3对数的杀灭能力。其作用机制尚不清楚。我们还没能分离出对主要的铅支架MBX 1066具有抗性的突变体。铅系列对革兰氏阴性感染的小鼠模型(ED50和lt；10 mg/kg)有效。此外，这些化合物在小鼠体内耐受性良好(MTD&GT；400 mg/kg)。最后，这些化合物的合成相对容易且价格低廉，而且具有非常有利的商品成本。这些总体特征促使这些化合物作为广谱抗菌剂迅速发展，用于对抗生物防御性A类和B类细菌病原体。在这一应用中，我们建议在合理的药物发现工作中对双吲哚铅系列进行化学优化，专注于提高对抗革兰氏阴性A和B类细菌威胁的广谱效力，在动物模型中展示有效性并建立作用机制。一旦最终选定临床候选药物，我们将在两个物种中进行IND-Enabling(GLP)药代动力学、毒理学和安全性药理学研究，并提交IND。相关性(见说明)：革兰氏阴性的A类和B类细菌生物防御病原体对美国构成严重威胁。当前治疗方法的数量和有效性非常有限，耐药性不断增加，以及故意改造抗生素耐药菌株的可能性表明，迫切需要开发能够对抗这些威胁的更有效、更广泛的新的抗菌剂。目标是开发一种新的化学类别的广谱治疗剂，用于对抗这些威胁。

DESCRIPTION (provided by applicant): The overall objective of this project is to develop a novel chemical class of broad-spectrum therapeutic agents, the bis-indole lead series, for use against Gram-negative category A and B bacterial biodefense threats, and file an IND by the end of the five year grant. The limited number and efficacy of current therapies, increasing drug resistance, and the possibility of deliberate engineering of antibiotic resistant strains argue for the urgent development of new more potent, broad-acting antibacterial agents capable of combating these biodefense threats. Compounds in this new chemical series exhibit broad-spectrum antibacterial activity, displaying potent inhibition (MICs of 0.3-.30ug/ml) of the growth of Gram-negative bacterial species, including a number of Category A and B agents such as Yersinia pestis, Francisella tularensis, Burkholderia mallei and pseudomallei. These compounds are also active against ciprofloxacin-resistant Bacillus anthracis (MIC 0.2-0.4ug/ml) and a variety of other Gram-positive and Gram-negative bacterial species. They act by a rapid bactericidal mechanism, exhibiting 3-log's of killing in 1-4 hours at concentrations near the MIC values. The mechanism of action is unknown. We have not been able to isolate mutants resistant to the primary lead scaffold MBX 1066. The lead series is effective in murine models of Gram-negative infections (ED50 <10 mg/kg). In addition, the compounds are well-tolerated in mice (MTD >400 mg/kg). Finally, these compounds are relatively easy and inexpensive to synthesize, with a very favorable cost of goods. These overall characteristics advocate for the rapid development of these compounds as broad spectrum antibacterial agents for use against biodefense category A and B bacterial pathogens. In this application, we propose to chemically optimize the bis-indole lead series in a rational drug discovery effort focused on improving broad-spectrum potency against gram-negative category A and B bacterial threats, demonstrate efficacy in animal models and establish the mechanism of action. Once a final clinical candidate has been chosen, we will conduct IND-enabling (GLP) pharmacokinetic, toxicology and safety pharmacology studies, in two species, and submit an IND. RELEVANCE (See instructions): Gram-negative category A and B bacterial biodefense pathogens represent a serious threat to the United States. The very limited number and efficacy of current therapies, increasing drug resistance, and the possibility of deliberate engineering of antibiotic resistant strains argue for the urgent development of new more potent, broad-acting antibacterial agents capable of combating these threats. The objective is to develop a new chemical class of broad-spectrum therapeutic agents for use against these threats