Preclinical development of Novo29, a new antibiotic

新型抗生素Novo29的临床前开发

• 批准号: 9914205
• 负责人: Losee Lucy Ling
• 金额: $ 98.74万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-10 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914205
• 关键词: Acute; Ames Assay; Animal Model; Anthrax disease; Anti-Bacterial Agents; Antibiotics; Bacillus anthracis; Back; Bacteremia; Bacteria; Binding; Biodistribution; Biological Availability; Cardiac; Cell Wall; Characteristics; Clinic; Clinical; Dose; Drug Interactions; Drug Kinetics; Drug resistance; Evaluation; Exposure to; Fermentation; Formulation; Goals; Grant; Health; Hospitals; Human; Hybrids; In Vitro; Incubated; Infection; Lead; Lipid III; Lipids; Liver Microsomes; Lung infections; Metabolic; Methods; Microbiology; Modeling; Modification; Multi-Drug Resistance; Mus; Oral; Pathogenicity; Peptides; Peptidoglycan; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Preparation; Production; Property; Proteobacteria; Public Health; Rattus; Regimen; Reporting; Resistance; Safety; Septicemia; Serial Passage; Serum; Site; Skin; Small Business Innovation Research Grant; Staphylococcus aureus; Streptococcus pneumoniae; Structure; Structure-Activity Relationship; Tail; Technology; Testing; Therapeutic; Thigh structure; Time; Tissues; Toxic effect; Toxicology; Work; analog; animal efficacy; antimicrobial; bactericide; base; design; drug discovery; drug resistant bacteria; genotoxicity; improved; in vitro Assay; in vivo; inhibitor/antagonist; inorganic phosphate; member; metabolic profile; methicillin resistant Staphylococcus aureus; microbial; microorganism; mouse model; multi-drug resistant pathogen; novel; pathogen; pre-clinical research; preclinical development; preclinical study; programs; repository; research and development; scaffold; undecaprenyl pyrophosphate; ventilator-associated pneumonia

The goal of this program is to continue developing our novel antimicrobial, Novo29, into a therapeutic for treating a wide range of infections caused by Gram-positive pathogens including Staphylococcus aureus, Streptococcus pneumoniae, and Bacillus anthracis. Using our iChip culturing technology, NovoBiotic has been exploiting previously uncultivable bacteria that make up 99% of all environmental microorganisms for production of new antibiotics. In 2015, NovoBiotic reported the discovery of teixobactin, the first member of a novel class of peptidoglycan synthesis inhibitors. We have since discovered Novo29, yet another promising and potent inhibitor of Gram-positive pathogens. Like teixobactin, Novo29 rapidly kills bacteria by inhibiting bacterial cell wall synthesis. However, Novo29 is significantly smaller than teixobactin, shows different target binding characteristics, and does not have serum gelation issues that require special formulations. Novo29 showed excellent efficacy against MRSA in two mouse models of infection (septicemia and thigh infection). The compound showed promising pharmacokinetic properties in mice, and is metabolically stable when incubated with liver microsomes. No spontaneous resistance (<10-10) occurred against S. aureus, and serial passaging in sublethal concentrations of drug failed to generate resistance. All these results demonstrate promising potential for Novo29 to treat drug-resistant infections. The goal of this project is to continue advancing Novo29 through preclinical research in preparation for IND-enabling studies. This work will include: (Aim 1) produce enough compound through fermentation to conduct all proposed studies in this grant, and for IND-enabling studies; (Aim 2) establish expanded MIC90s for pathogens isolated from recent clinical infections. Determine MBCs, time-kill profiles and post antibiotic effect (PAE) against relevant pathogens; (Aim 3) continue evaluating toxicity and pharmacokinetic (PK) profiles in animal models. Identify and characterize any major microsomal metabolites. Evaluate drug-drug interactions, genotoxicity, and cardiac safety in in vitro assays. Determine which PK/PD parameter(s) best correlate with efficacy; (Aim 4) examine efficacy of Novo29 in animal models of pulmonary infection with MRSA and anthrax; (Aim 5) explore the structure activity relationship (SAR) of Novo29 through medicinal chemistry. Design and test back-up analogs that may have increased potency and oral bioavailability. At the conclusion of this grant, Novo29 will be prepared to enter formal IND-enabling studies and advance to the clinic.

该计划的目标是继续将我们的新型抗菌药物 Novo29 开发成治疗药物 用于治疗由包括金黄色葡萄球菌在内的革兰氏阳性病原体引起的多种感染， 肺炎链球菌和炭疽杆菌。 利用我们的 iChip 培养技术，NovoBiotic 一直在开发以前无法培养的细菌， 占用于生产新抗生素的所有环境微生物的 99%。 2015年，NovoBiotic报道 Teixobactin 的发现，是一类新型肽聚糖合成抑制剂的第一个成员。我们有 自从发现Novo29以来，Novo29是另一种有前途且有效的革兰氏阳性病原体抑制剂。喜欢 teixobactin、Novo29 通过抑制细菌细胞壁合成来快速杀死细菌。然而，Novo29 是 明显小于 teixobactin，显示出不同的靶点结合特性，并且不具有血清 需要特殊配方的凝胶化问题。 Novo29 在两只小鼠体内表现出优异的抗 MRSA 功效 感染模型（败血症和大腿感染）。该化合物显示出有前景的药代动力学 小鼠体内的特性，并且与肝微粒体一起孵育时代谢稳定。无自发抵抗 (<10-10) 针对金黄色葡萄球菌发生，并且以亚致死浓度的药物连续传代未能产生 反抗。所有这些结果都表明 Novo29 在治疗耐药感染方面具有广阔的潜力。 该项目的目标是通过临床前研究继续推进 Novo29 的发展，为 支持 IND 的研究。这项工作将包括：（目标 1）通过发酵产生足够的化合物来进行 本次拨款中的所有拟议研究以及 IND 支持研究； （目标 2）建立针对病原体的扩展 MIC90 从最近的临床感染中分离出来。确定 MBC、时间杀死曲线和抗生素后效应 (PAE) 相关病原体； （目标 3）继续评估动物模型中的毒性和药代动力学 (PK) 特征。 鉴定并表征任何主要微粒体代谢物。评估药物间相互作用、遗传毒性和 体外测定中的心脏安全性。确定哪些 PK/PD 参数与疗效最相关； （目标 4） 检查 Novo29 在 MRSA 和炭疽肺部感染动物模型中的功效； （目标 5）探索 通过药物化学分析Novo29的结构活性关系（SAR）。设计和测试备用类似物 这可能会增加效力和口服生物利用度。 这笔赠款结束后，Novo29 将准备进入正式的 IND 支持研究，并 提前到诊所。