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Novo29，使其成为一种治疗性药物 用于治疗由革兰氏阳性病原体引起的广泛感染，包括金黄色葡萄球菌， 肺炎链球菌和炭疽杆菌。 使用我们的iChip培养技术，新生物公司一直在利用以前无法培养的细菌 占生产新抗生素的所有环境微生物的99%。2015年，新生物公司报告说 发现了新的肽聚糖合成抑制剂中的第一个成员teixobactin。我们有 自发现Novo29以来，又发现了另一种有希望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的合成快速杀死细菌。然而，Novo29是 显著小于teixobactin，表现出不同的靶向结合特性，并且没有血清 需要特殊配方的凝胶问题。Novo29对两只小鼠的耐甲氧西林金黄色葡萄球菌有良好的疗效 感染模式(败血症和大腿感染)。该化合物显示出良好的药代动力学 在小鼠体内的性质，并在与肝脏微生物体孵育时代谢稳定。无自发抵抗 (&lt；10-10)发生在金黄色葡萄球菌身上，并且在亚致死浓度药物的连续传代中未能产生 抵抗。所有这些结果表明，Novo29在治疗耐药感染方面具有良好的潜力。 该项目的目标是通过临床前研究继续推进Novo29，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进行 这笔赠款中的所有拟议研究，以及支持IND的研究；(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的。测定MBCs、时间-杀伤率和抗生素后效应(PAE) 相关病原体；(目标3)继续在动物模型中评估毒性和药代动力学(PK)曲线。 识别和表征任何主要的微生物体代谢物。评估药物相互作用、遗传毒性和 体外心脏安全性试验。确定哪个PK/PD参数(S)与疗效最相关；(目标4) 检测Novo29在MRSA和炭疽病肺部感染动物模型中的疗效；(目标5)探索 通过药物化学研究Novo29的构效关系(SAR)。设计和测试备份模拟 这可能提高了药效和口服生物利用度。 在这笔赠款结束时，Novo29将准备进入正式的IND使能研究和 前进到诊所去。

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.