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: 10231210
• 负责人: Michelle M. Butler
• 金额: $ 105.26万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231210
• 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; efficacious treatment; 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 将 MDR 淋病奈瑟菌 (Ng) 列为三种最紧迫的抗生素耐药性之一 美国的威胁。 Ng 是一种革兰氏阴性挑剔微生物，它会导致淋病，这是第二大疾病 美国普遍存在性传播细菌感染 (STI)，估计病例数超过 800,000 例 每年。如果不及时治疗，淋病会导致女性盆腔炎，从而导致输卵管 疤痕和不育或可能扩散，引起关节和皮肤表现。一旦可以轻松治疗，吴恩达 对几乎所有用于治疗该病的抗生素都产生了耐药性，留下了阿奇霉素 (AZM) 和 头孢曲松（CTX）是目前唯一可用的治疗选择。重要的是，最近出现了一系列病例 据夏威夷报道，该病毒对 AZM 和 CTX 均具有抗药性，突显了对新产品的迫切需求 针对抗生素耐药性 Ng 感染的治疗方法。 细菌翻译受到转录错误、mRNA 损伤和翻译移码的困扰 导致不间断核糖体复合物的事件，防止蛋白质产物的释放并进一步抑制 翻译。不间断复合物的恢复是由反式翻译、ArfA 介导的重要细菌过程 或 ArfB 作用于所有已测序细菌基因组中高度保守的细菌核糖体区域。 在初步研究中，我们证明基于恶二唑的化合物可以抑制不间断的核糖体救援， 作为针对包括 Ng 在内的一系列病原体的有效抗菌剂，针对 Ng 的 MIC90 值 范围为 0.8-1.6 µM (0.25-0.54 µg/mL)。这些化合物对哺乳动物的毒性极小 在 F. tularensis 小鼠模型中具有出色的药代动力学和体内抗生素活性。 本提案的目的是将不间断核糖体救援的先导恶二唑抑制剂优化为 一类新型广谱治疗剂，用于对抗淋病奈瑟菌并 推动该化合物走向研究性新药 (IND) 支持的 GLP 毒理学和安全性 药理学研究和预 IND 提交。为了实现这一目标，我们将实现七个具体目标 目标：在目标 1 中，我们将通过 SAR 驱动的模拟生成来优化先导序列。在目标 2 中，我们将 通过体外生物学和 ADME 评估优先考虑先导系列类似物。在目标 3 中，我们将确认并 进一步探讨恶二唑抑制剂对Ng不间断核糖体救援的作用机制和特异性。 在目标 4 中，我们将根据体内特性选择临床前候选药物和备用药物。在目标 5 中，我们将 开展支持 IND 的药代动力学、毒理学和安全药理学研究。在目标 6 中我们将执行 CMC 研究，针对 GMP 制造商的 1 个非 GMP 原料药贴片。在目标 7 中，我们将要求 与 FDA 举行的 IND 前会议。