A new class of broad-spectrum antibacterials for treating MDR infections

用于治疗耐多药感染的新型广谱抗菌药物

• 批准号: 10382405
• 负责人: Charles Testa
• 金额: $ 100万
• 依托单位: CURZA INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382405
• 关键词: Advanced Development; Ames Assay; Anti-Bacterial Agents; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Bacterial Proteins; Binding; Binding Proteins; Biochemical; Biological Assay; Breathing; Canis familiaris; Cells; Chemicals; Clinical; Complex; Crystallization; Cytochromes; Data; Dose; Dose Fractionation; Drug Compounding; Drug Design; Drug Kinetics; Engineering; Enterobacteriaceae; Escherichia coli; Evaluation; Exhibits; Frequencies; Gram-Negative Bacteria; HepG2; In Vitro; Infection; Investigational Drugs; Klebsiella pneumoniae; Lead; Link; Liver Microsomes; Mammalian Cell; Maximum Tolerated Dose; Metabolic; Methods; Microbiology; Mitochondria; Modeling; Multi-Drug Resistance; Mus; Mutation; Mycobacterium tuberculosis; Natural Products; No-Observed-Adverse-Effect Level; Pharmaceutical Preparations; Pharmacology; Phase; Plasma Proteins; Property; Protein Biosynthesis; Pseudomonas aeruginosa; Rattus; Resistance; Resistance development; Ribosomes; Rodent; Roentgen Rays; Safety; Serial Passage; Serum; Serum Proteins; Site; Source; Structure; Testing; Therapeutic Index; Thermus thermophilus; Thigh structure; Time; Toxic effect; Toxicokinetics; Toxicology; Urinary tract infection; analog; base; carbapenem resistance; clinical candidate; cytotoxicity; drug candidate; drug efficacy; efficacy testing; experimental study; genotoxicity; improved; in vitro Assay; in vitro activity; in vivo; indexing; inhibitor; lead optimization; lead series; methicillin resistant Staphylococcus aureus; micronucleus; mouse model; multi-drug resistant pathogen; novel antibiotic class; novel therapeutics; pathogen; pathogenic bacteria; pharmacokinetics and pharmacodynamics; pharmacophore; pre-clinical; programs; receptor binding; resistance frequency; resistant strain; response

Project Summary Cūrza is developing a new class of broad-spectrum antibiotic, with a focus on multidrug-resistant (MDR) Enterobacteriaceae. The CZ-02 program is directed towards compounds that bind to a unique site on the bacterial ribosome that is not targeted by existing antibiotics and is therefore not expected to encounter cross- resistance to other antibiotics used clinically. Inspired by a natural product identified as a lead for Mycobacterium tuberculosis (Mtb), analogs have been developed that selectively inhibit bacterial protein synthesis, with little effect on mammalian protein synthesis, through a binding interaction with the ribosome at a heretofore un- drugged site. The genesis and progression of the CZ-02 program reflect a compelling argument in support of natural products as a source of new therapeutic leads. The natural product identified as a lead has multiple metabolic liabilities and minimal activity against Gram-positive and Gram-negative pathogens in vitro, and likely in vivo. However, after re-engineering the natural product’s minimum pharmacophore responsible for activity into new chemical matter the resulting compounds are metabolically stable, exhibit exquisite selectivity and potency for bacterial protein synthesis and are efficacious against MDR pathogens in vitro and in vivo - all while displaying a lack of cytotoxicity toward mammalian cells. The proposed Direct-to-Phase II project will ultimately develop a new antibacterial drug candidate that is potent with broad spectrum activity, focusing on Gram-negative pathogens that will be at the IND preparation stage. Advancement of this antibacterial lead series for an initial UTI clinical indication will be accomplished by the following aims. Aim 1 will optimize advanced leads for enhanced efficacy in infection models with MDR Gram- negative pathogens. Curza’s proprietary model for producing potent and selective inhibitors of bacterial P-site protein synthesis, in combination with numerous activity assays (biochemical, microbiological, in vitro ADME- Tox), will be used to guide optimization efforts and eliminate compounds with potential safety liabilities. Aim 2 will define pharmacokinetics of optimized leads while identifying the maximum tolerated dose, which will guide efficacy testing in thigh infection models to select 3 compounds for evaluation in urinary tract infection models. A lead and backup drug candidate will be selected in Aim 3 by evaluation in UTI models of antibiotic-resistant bacteria and the optimal dosing strategy will be determined from PKPD studies. Aim 4 will ultimately establish the safety of the lead using non-GLP and GLP methods.

项目摘要 CūRZA正在开发一种新的广谱抗生素，重点是多药耐药(MDR) 肠杆菌科。CZ-02计划针对的是与化合物上的唯一位置结合的化合物 细菌核糖体不是现有抗生素的靶标，因此预计不会遇到交叉 对临床上使用的其他抗生素产生耐药性。灵感来自一种被确定为分枝杆菌铅的天然产品 结核病(Mtb)，已经开发出选择性地抑制细菌蛋白质合成的类似物，几乎没有 对哺乳动物蛋白质合成的影响，通过与核糖体的结合相互作用，在迄今没有. 被下药的网站。CZ-02计划的起源和发展反映了一个令人信服的论点，支持 天然产品作为新的治疗线索的来源。被确认为铅的天然产品有多个 体外对革兰氏阳性和革兰氏阴性病原体的代谢敏感性和最低活性 在活体内。然而，在重新设计天然产品负责活动的最小药效基团后， 新的化学物质生成的化合物代谢稳定，表现出极好的选择性和效力 用于细菌蛋白质合成，在体外和体内对MDR病原体有效-所有这些都在展示 对哺乳动物细胞缺乏细胞毒性。拟议的直接到第二阶段项目最终将开发一个 广谱抗菌药候选新药，关注革兰氏阴性 将处于IND准备阶段的病原体。 这一抗菌铅系列在最初的UTI临床适应症方面的进展将由 遵循目标。AIM 1将优化高级线索，以增强MDR Gram感染模型的疗效 阴性病原体。Curza生产细菌P-位点的有效和选择性抑制剂的专利模型 蛋白质合成，结合多种活性分析(生化、微生物、体外ADME- 毒素)，将用于指导优化工作并消除具有潜在安全隐患的化合物。目标2 将在确定最大耐受量的同时定义优化的先导药物的药代动力学，这将指导 在大腿感染模型中进行有效性测试，以选择3种化合物用于尿路感染模型的评估。 在目标3中，将通过对抗生素耐药性的UTI模型进行评估来选择候选的主药和备用药物 细菌和最佳剂量策略将从PKPD研究中确定。目标4最终将确立 使用非GLP和GLP方法检测铅的安全性。