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

项目摘要 科萨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计划针对的是结合到细胞上的独特位点的化合物。 细菌核糖体不被现有抗生素靶向，因此预计不会遇到交叉， 对临床使用的其他抗生素耐药。灵感来自一种被鉴定为分枝杆菌先导的天然产物 针对结核分枝杆菌（Mtb），已经开发了选择性抑制细菌蛋白质合成的类似物， 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， 吸毒网站CZ-02计划的起源和进展反映了一个令人信服的论点， 天然产品作为新治疗线索的来源。被鉴定为铅的天然产物具有多个 体外对革兰氏阳性和革兰氏阴性病原体的代谢倾向和最小活性， in vivo.然而，在将天然产物负责活性的最小药效团重新设计成 新的化学物质，所产生的化合物是代谢稳定的，表现出精致的选择性和效力 用于细菌蛋白质合成，并在体外和体内有效对抗MDR病原体-所有这些同时显示 缺乏对哺乳动物细胞的细胞毒性。拟议的直接进入第二阶段项目最终将开发一个 新的抗菌药物候选物，具有广谱活性，重点是革兰氏阴性菌 将处于IND准备阶段的病原体。 该抗菌电极导线系列用于初始UTI临床适应症的进展将由 的目标。目标1将优化先进的电极导线，以增强MDR革兰氏感染模型的疗效- 阴性病原体。Curza的专利模型，用于生产细菌P位点的有效和选择性抑制剂 蛋白质合成，结合许多活性测定（生物化学、微生物、体外ADME- 毒性），将用于指导优化工作，并消除具有潜在安全责任的化合物。目的2 将定义优化导联的药代动力学，同时确定最大耐受剂量，这将指导 在大腿感染模型中进行功效测试，以选择3种化合物用于在尿路感染模型中进行评价。 在目标3中，将通过在耐药的UTI模型中进行评价，选择先导和备用候选药物。 细菌和最佳给药策略将从PKPD研究中确定。目标4将最终建立 使用非GLP和GLP方法的电极导线安全性。

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.