Oxadiazole Inhibitors of Non-Stop Ribosome Rescue to treat MDR Neisseria gonorrhoeae

不间断核糖体救援恶二唑抑制剂治疗耐多药淋病奈瑟菌

• 批准号: 9975690
• 负责人: Zachary David Aron
• 金额: $ 105.81万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-18 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975690
• 关键词: Animal Model; Annual Reports; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Azithromycin; Bacteria; Bacterial Genome; Bacterial Infections; Binding; Biochemical; Biological Availability; Biology; Case Study; Ceftriaxone; Centers for Disease Control and Prevention (U.S.); Chemicals; Chemistry; Cicatrix; Clinic; Clinical; Clinical Trials; Communication; Complex; Data; Development; Drug Kinetics; Drug-resistant Neisseria Gonorrhoeae; Engineering; Ensure; Evaluation; Event; Exhibits; Formulation; Francisella tularensis; Future; Generations; Genetic Transcription; Gonorrhea; Hawaii; Health; Hour; Human; In Vitro; Infection; Infertility; Investigational Drugs; Joints; Lead; Left; Liver Microsomes; Mammalian Cell; Mammalian Oviducts; Manufacturer Name; Mediating; Messenger RNA; Metabolic; Mitochondria; Multi-Drug Resistance; Mycobacterium tuberculosis; Neisseria gonorrhoeae; Organism; Oxadiazoles; Pathway interactions; Pelvic Inflammatory Disease; Permeability; Pharmaceutical Preparations; Pharmacology Study; Photoaffinity Labels; Process; Property; Proteins; Rattus; Recovery; Reporting; Research; Resistance; Ribosomal Frameshifting; Ribosomes; Risk; Route; Running; Safety; Serum; Sexual Transmission; Site; Skin Manifestations; Solubility; Specificity; Terminator Codon; Therapeutic Agents; Therapeutic Index; Toxic effect; Toxicology; Translations; United States; Woman; analog; antimicrobial; base; clinical development; drug discovery; experimental study; improved; in vivo; indexing; inhibitor/antagonist; lead optimization; lead series; meetings; methicillin resistant Staphylococcus aureus; mouse model; new therapeutic target; novel; novel therapeutics; pathogen; physical property; pre-clinical; preclinical study; prevent; resistance mechanism; therapeutic development; therapeutic target

Abstract The CDC lists MDR Neisseria gonorrhoeae (Ng) as one of the three most urgent antibiotic resistance threats in the United States. A Gram-negative fastidious organism, Ng causes gonorrhea, the second-most prevalent sexually transmitted bacterial infection (STI) with >800,000 estimated cases in the United States annually. Left untreated, gonorrhea can cause pelvic inflammatory disease in women, leading to fallopian tube scarring and infertility or may disseminate, causing joint and skin manifestations. Once easily treatable, Ng has evolved resistance to nearly every antibiotic used to treat it, leaving a combination of azithromycin (AZM) and ceftriaxone (CTX) as the only currently available treatment option. Importantly, a cluster of cases was recently reported in Hawaii that was resistant to both AZM and CTX, highlighting the critical need for new therapeutics targeting antibiotic-resistant Ng infections. Bacterial translation is plagued by transcription errors, mRNA damage, and translational frameshifting events that result in non-stop ribosome complexes, preventing release of protein products and inhibiting further translation. Recovery of non-stop complexes is a crucial bacterial process mediated by trans-translation, ArfA or ArfB acting on a region of the bacterial ribosome highly conserved across all sequenced bacterial genomes. In preliminary studies, we demonstrated that oxadiazole-based compounds inhibit non-stop ribosome rescue, acting as potent antimicrobials against a range of pathogens, including Ng, with MIC90 values against Ng ranging from 0.8-1.6 µM (0.25-0.54 µg/mL). These compounds exhibit minimal toxicity towards mammalian cells, excellent pharmacokinetics and in vivo antibiotic activity in a F. tularensis mouse model. The objective of this proposal is to optimize the lead oxadiazole inhibitor of non-stop ribosome rescue into a novel class of broad-spectrum therapeutic agents for use against Neisseria gonorrhoeae and to advance this compound towards Investigational New Drug (IND)-enabling GLP toxicology and safety pharmacology studies and pre-IND submission. We will accomplish seven specific aims to achieve this objective: In Aim 1 we will optimize the lead series through SAR-driven analog generation. In Aim 2 we will prioritize lead series analogs through in vitro biology and ADME evaluations. In Aim 3 we will confirm and further explore mechanism of action and specificity of oxadiazole inhibitors of non-stop ribosome rescue in Ng. In Aim 4 we will select a preclinical candidate and backup based on in vivo properties. In Aim 5 we will conduct IND-enabling pharmacokinetic, toxicology and safety pharmacology studies. In Aim 6 we will perform CMC studies, targeting 1 non-GMP patch of drug substance at a GMP manufacturer. In Aim 7 we will request a pre-IND meeting with the FDA.

抽象的 CDC列出了MDR Neiserseria Gonorrhoeae（NG）为三种最紧急的抗生素耐药性之一 美国的威胁。革兰氏阴性的挑剔生物，NG导致淋病，第二大生物 在美国，普遍的性传播细菌感染（STI）估计为800,000例 剩下的未治疗，淋病可能引起妇女骨盆炎症性疾病，导致输卵管 疤痕和不育或可能传播，导致关节和皮肤表现。一旦很容易治疗，ng就有 对几乎所有用于治疗它的抗生素的耐药性进化，留下了阿奇霉素（AZM）和 头孢曲松（CTX）是唯一可用的治疗选择。重要的是，最近有一组案例 在夏威夷报道了对AZM和CTX具有抵抗力的报道，强调了对新的关键需求 靶向抗抗生素NG感染的治疗剂。 细菌翻译受到转录误差，mRNA损伤和翻译框架的困扰 导致不间断核糖体复合物，防止蛋白质产物释放并进一步抑制的事件 翻译。恢复非停车络合物是通过反译本介导的至关重要的细菌过程 或作用于在所有测序细菌基因组中高度构成细菌核糖体区域的ARFB。 在初步研究中，我们证明了基于黄唑的化合物抑制了不间断的核糖体救援， 充当针对一系列病原体（包括NG）的潜在抗菌剂，MIC90值针对NG 范围为0.8-1.6 µm（0.25-0.54 µg/ml）。这些化合物暴露于对哺乳动物的最小毒性 细胞，优秀的药代动力学和f菌小鼠模型中的体内抗生素活性。 该提案的目的是优化不间断核糖体救援的铅氧化二唑抑制剂 一类新颖的广谱治疗剂，用于对抗淋病的奈瑟氏菌 将这种化合物推向研究性新药（IND） - 增强GLP毒理学和安全性 药理学研究和预先提交。我们将实现七个特定目标来实现这一目标 目的：在AIM 1中，我们将通过SAR-priven模拟生成优化铅序列。在目标2中，我们将 通过体外生物学和ADME评估确定铅序列类似物的优先级。在AIM 3中，我们将确认并 进一步探讨了NG中非停车核糖体救援的黄二唑抑制剂的作用机理和特异性。 在AIM 4中，我们将根据体内特性选择临床前候选和备份。在目标5中，我们将 进行指定药代动力学，毒理学和安全药理学研究。在AIM 6中，我们将表演 CMC研究，针对GMP制造商的1个非GMP药物斑块。在AIM 7中，我们将要求 与FDA的预先开会。