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

描述（由申请人提供）：本项目的总体目标是开发一种新的化学类广谱治疗剂，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，并在五年资助期结束前提交IND。目前治疗的数量和功效有限，耐药性增加，以及抗生素耐药菌株的故意工程的可能性，迫切需要开发能够对抗这些生物防御威胁的新的更有效，更广泛作用的抗菌剂。该新化学系列中的化合物表现出广谱抗菌活性，显示出对革兰氏阴性细菌物种的生长的有效抑制（MIC为0.3- 0.30 μ g/ml），包括许多A和B类试剂，如鼠疫耶尔森氏菌、土拉热弗朗西丝氏菌、鼻疽伯克霍尔德氏菌和类鼻疽杆菌。这些化合物还对环丙沙星抗性炭疽杆菌（MIC 0.2-0.4ug/ml）和多种其它革兰氏阳性和革兰氏阴性细菌物种具有活性。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小时内显示出3个对数的杀灭。作用机制未知。我们还不能分离出对主要先导支架MBX 1066有抗性的突变体。铅系列在革兰氏阴性菌感染的小鼠模型中有效（ED 50 <10 mg/kg）。此外，所述化合物在小鼠中耐受良好（MTD >400 mg/kg）。最后，这些化合物合成相对容易且便宜，具有非常有利的商品成本。这些总体特征促进了这些化合物作为用于对抗生物防御A类和B类细菌病原体的广谱抗菌剂的快速发展。在本申请中，我们提出在合理的药物发现努力中对双吲哚铅系列进行化学优化，所述药物发现努力集中于提高针对革兰氏阴性A类和B类细菌威胁的广谱效力，在动物模型中证明功效并建立作用机制。一旦选择了最终临床候选物，我们将在两个种属中进行IND使能（GLP）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）：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。目前治疗的数量和功效非常有限，耐药性增加，以及故意工程化抗生素耐药菌株的可能性，迫切需要开发能够对抗这些威胁的新的更有效，更广泛作用的抗菌剂。其目的是开发一种新的化学类广谱治疗剂，用于应对这些威胁

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