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广谱治疗剂，双吲哚铅系列，用于对抗革兰氏阴性a类和B类细菌生物防御威胁，并在五年资助结束前提交IND。当前治疗方法的数量和疗效有限，不断增加的耐药性，以及有意设计抗生素耐药菌株的可能性，表明迫切需要开发新的更有效、更广泛的抗菌剂，能够对抗这些生物防御威胁。这一新的化学系列化合物具有广谱抗菌活性，对革兰氏阴性细菌的生长表现出强有力的抑制作用（MICs为0.3- 0.30 ug/ml），包括许多a类和B类细菌，如鼠疫耶尔森菌、土拉菌弗朗西菌、马氏伯克氏菌和假麦氏菌。这些化合物对耐环丙沙星的炭疽芽孢杆菌（MIC 0.2-0.4ug/ml）和多种其他革兰氏阳性和革兰氏阴性细菌也有活性。它们通过快速杀菌机制起作用，在接近MIC值的浓度下，在1-4小时内表现出3对数的杀灭效果。其作用机制尚不清楚。我们还没能分离出对初级铅支架MBX 1066有抗性的突变体。铅系列对革兰氏阴性感染小鼠模型（ED50 <10 mg/kg）有效。此外，这些化合物在小鼠体内具有良好的耐受性（MTD为100 ~ 400 mg/kg）。最后，这些化合物的合成相对容易和便宜，具有非常有利的商品成本。这些总体特性促使这些化合物作为广谱抗菌剂迅速发展，用于生物防御A类和B类细菌病原体。在这项应用中，我们建议在合理的药物发现工作中对双吲哚先导系列进行化学优化，重点是提高抗革兰氏阴性a类和B类细菌威胁的广谱效力，在动物模型中证明其有效性并建立作用机制。一旦最终的临床候选药物被选定，我们将在两个物种中进行使能GLP的药代动力学、毒理学和安全药理学研究，并提交IND。相关性（见说明书）：革兰氏阴性a类和B类细菌生物防御病原体对美国构成严重威胁。目前的治疗方法数量和疗效都非常有限，不断增加的耐药性以及有意设计抗生素耐药菌株的可能性表明，迫切需要开发新的更有效、更广泛的抗菌剂，能够对抗这些威胁。目标是开发一种新的化学类广谱治疗剂，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