Preclinical development of Novo29, a new antibiotic

该计划的目标是继续开发我们的新型抗菌剂Novo 29， 用于治疗由包括金黄色葡萄球菌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一直在利用以前无法培养的细菌， 占所有环境微生物的99%，用于生产新的抗生素。2015年，NovoBiotic报告称， 发现了teixobactin，这是一类新的肽聚糖合成抑制剂的第一个成员。我们有 自发现Novo 29以来，Novo 29是革兰氏阳性病原体的另一种有前途的有效抑制剂。像 Novo 29通过抑制细菌细胞壁的合成而迅速杀死细菌。然而，Novo 29是 显著小于teixobactin，显示不同的靶结合特征，并且不具有血清 需要特殊配方的凝胶化问题。Novo 29在两只小鼠中显示出对MRSA的优异疗效 感染模型（败血症和大腿感染）。该化合物显示出良好的药代动力学 在小鼠中的性质，并且当与肝微粒体孵育时代谢稳定。无自发抵抗 （<10-10）。金黄色葡萄球菌，并在亚致死浓度的药物连续传代未能产生 阻力所有这些结果表明Novo 29治疗耐药感染的潜力很大。 本项目的目标是通过临床前研究继续推进Novo 29，为 国家研究开发扶持性研究。本研究工作包括：（目的1）通过发酵生产足够的化合物， 本补助金中的所有拟议研究，以及IND使能研究;（目标2）建立病原体的扩展MIC 90 从最近的临床感染中分离出来。测定MBC、时间杀灭曲线和抗生素后效应（PAE）， （目的3）继续评价动物模型中的毒性和药代动力学（PK）特征。 鉴别和表征任何主要微粒体代谢物。评价药物相互作用、遗传毒性和 体外试验中的心脏安全性。确定哪些PK/PD参数与疗效最相关;（目的4） 检测Novo 29在MRSA和炭疽肺部感染动物模型中的有效性;（目的5）探索 通过药物化学研究Novo 29的构效关系。设计和测试备份模拟器 其可能具有增加的效力和口服生物利用度。 在该资助结束时，Novo 29将准备进入正式的IND使能研究， 提前到诊所。

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.