Development of a mechanistically novel Gram-negative antibiotic targeting MsbA-mediated Lipopolysaccharide Biogenesis

开发一种机制新颖的革兰氏阴性抗生素，靶向 MsbA 介导的脂多糖生物发生

基本信息

批准号：
10584170
负责人：
Terry Roemer
金额：
$ 67.93万
依托单位：
PROKARYOTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-04 至 2027-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584170
关键词：
ATP-Binding Cassette Transporters Address American Anti-Bacterial Agents Antibiotic susceptibility Antibiotics Bacterial Infections Binding Proteins Biochemical Biogenesis Cell Survival Cells Chemicals Clinical Coculture Techniques Communities Complex Cytoplasm Development Dose Drug Design ESKAPE pathogens Economic Burden Enterobacteriaceae Enterobacteriaceae Infections Enzymes Equation Escherichia coli Escherichia coli Infections European Extended-spectrum β-lactamase Formulation Fright Goals HepG2 Hepatocyte Hospitalization Hospitals In Vitro Incidence Infection Ion Channel Kidney Klebsiella pneumoniae Lactamase Lactams Lead Left Life Lipid A Lipopolysaccharides Marketing Measures Mediating Membrane Membrane Proteins Microsomes Modeling Monitor Multi-Drug Resistance Mus New Agents Nosocomial Infections O Antigens Outpatients Pathway interactions Patients Peritonitis Pharmaceutical Preparations Phase Plasma Plasma Proteins Property Resistance Resolution Roentgen Rays Series Structure Structure-Activity Relationship Superbug Testing Therapeutic Time Urinary tract infection acute pyelonephritis analog bactericide carbapenem resistance carbapenem-resistant Enterobacteriaceae clinical development community setting cost cytotoxicity fluoroquinolone resistance improved in vitro testing in vivo indexing inhibitor innovation lead optimization lead series meetings membrane biogenesis minimal inhibitory concentration novel overexpression pathogen periplasm pharmacokinetics and pharmacodynamics pre-clinical programs resistance frequency safety study scale up small molecule small molecule inhibitor subcutaneous synergism trend

项目摘要

Recently, WHO and CDC designated Carbapenem-resistant Enterobacteriaceae (CRE) a Priority 1 ‘critical superbug’ and an ‘Urgent Threat’, and warned that new treatments for superbugs, which kill nearly 50,000 Americans and Europeans a year, are unlikely to be developed in time if left to market forces alone. Few therapeutic options are left to treat CRE, and the fear of ‘pan-resistant’ CRE has emerged. Currently, most CRE infections occur in a hospital setting, but the potential spread of CRE in the community also exists. Entirely new agents with novel mechanisms of action languish; completely novel antibacterials with a new mechanism of action and lacking clinical cross-resistance to existing drug classes are urgently needed. Our proposal aims to develop a mechanistically novel, IV and PO administered agent to treat uncomplicated and complicated UTI cases caused by antibiotic susceptible and multidrug-resistant Enterobacteriaceae, including extended spectrum beta-lactamase producers and CRE. Using an innovative overexpression-based co-culture screen in Escherichia coli (Ec), we identified four structurally distinct series of small molecule inhibitors targeting MsbA, an essential and broadly conserved Gram-negative (GN) ABC transporter responsible for lipopolysaccharide (LPS) biogenesis and construction of the Gram-negative outer membrane (OM). A prioritization of the four series through our current R21AI146541-supported program has enabled selection of a series to enter the Lead Identification (ID) phase of development. We propose the following aims to develop this series: Aim 1 (2 years) - Lead ID to select a single lead series with WT activity and efficacy for Aim 2 Lead Optimization (Op): 1.1) exploratory med chem to improve WT activity, 1.2) obtain high resolution MsbAi-MsbA X-ray co-crystal structure to guide structure-based drug design (SBBD) using the Schrodinger Discover Suite, 1.3) monitor whole cell (MIC) activity, 1.4) track in vitro IC50 potency, 1.5) test ppb, mammalian cytotoxicity, and P-gp inhibition/stimulation, 1.6) FOR, time kill curves, and LpxC inhibitor synergy studies, 1.7) measure PK, 1.8) determine Enterobacteriaceae MIC90, 1.9) synthetic scale up, 1.10) dose-ranging mouse PK/formulation studies, and 1.11) demonstrate in vivo efficacy in a mouse peritonitis model of WT Ec infection. Aim 2 (3 years) - Lead Op to prepare a Pre-Clinical Candidate (PCC) for subsequent safety studies: 2.1) med chem optimization of drug-like properties, 2.2) track MIC, IC50, and cytotoxicity, 2.3) conduct in vitro ADME, 2.4) single mouse (IV, IP, PO) PK, 2.5) validate MOA and FOR, 2.6) test in vitro mammalian off target-activity, 2.7) expanded Enterobacteriaceae MIC90, 2.8) dose-ranging mouse PK, 2.9) synthetic scale up, 2.10) efficacy in murine UTI model, 2.11) identify PK/PD index, 2.12) expanded off target-activity as in 2.6.

最近，谁和疾病预防控制中心设计了耐碳青霉烯的肠杆菌科（CRE）优先级1' Superbug’和“紧急威胁”，并警告说，对超级细菌的新疗法杀死了近50,000 如果只留给市场力量，那么美国和欧洲人每年就不太可能及时发展。很少治疗选择要治疗CRE，并且出现了对“耐泛力” CRE的恐惧。目前，大多数Cre 感染发生在医院环境中，但是CRE在社区中的潜在传播也存在。全新具有新颖动作机制的特工；具有新机制的完全新颖的抗菌物迫切需要采取行动和缺乏对现有药物类别的临床抗性。我们的建议目标开发一种机械新颖的IV和PO给药的剂来处理简单且复杂的UTI 由抗生素易感和抗多药肠杆菌科引起的病例，包括扩展光谱 β-内酰胺酶生产商和CRE。使用Escherichia中基于创新的过表达的共培养屏幕大肠杆菌（EC），我们确定了针对MSBA的四个结构上不同的小分子抑制剂，这是必不可少的以及负责脂多糖（LPS）的广泛保守的革兰氏阴性（GN）ABC转运蛋白革兰氏阴性外膜的生物发生和结构（OM）。四个系列的优先级通过我们当前的R21AI146541支持的程序，已启用了一个系列的选择来进入铅识别（ID）发展阶段。我们提出以下目标来开发该系列： AIM 1（2年） - 铅ID选择具有WT活动的单个铅系列和AIM 2铅的效率优化（OP）：1.1）探索性药物以改善WT活性，1.2）获得高分辨率MSBAI-MSBA X射线共晶结构，使用Schrodinger Discover Suite指导基于结构的药物设计（SBBD）， 1.3）监测全细胞（MIC）活性，1.4）在体外IC50效力，1.5）测试PPB，哺乳动物细胞毒性和 P-gp抑制/刺激，1.6），用于时间杀死曲线和LPXC抑制剂协同研究，1.7）测量PK，1.8）确定肠杆菌科MIC90，1.9）合成尺度，1.10）剂量范围小鼠PK/配方研究， 1.11）在WT EC感染的小鼠腹膜炎模型中证明了体内效率。 AIM 2（3年） - 领导OP准备临床前候选者（PCC）进行后续安全研究：2.1）药物样性质的Med Chem优化，2.2）轨道MIC，IC50和细胞毒性，2.3）在体外进行进行， 2.4）单小鼠（iv，ip，po）pk，2.5）验证MOA和2.6）测试体外哺乳动物的目标活性， 2.7）扩展的肠杆菌科MIC90，2.8）剂量范围的小鼠PK，2.9）合成尺度，2.10）EaseAcy 在Murine UTI模型中，2.11）识别PK/PD指数，2.12）如2.6中的目标活性扩大。