Synthetic Antimicrobial Peptoids for Treatment of Chronic Suppurative Otitis Media

用于治疗慢性化脓性中耳炎的合成抗菌肽

• 批准号: 10384258
• 负责人: Annelise Emily Barron
• 金额: $ 25.65万
• 依托单位: MAXWELL BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384258
• 关键词: Affect; Animal Model; Anti-Infective Agents; Antimicrobial Resistance; Bacteria; Biological; Biological Availability; Biological Sciences; Biomedical Engineering; Cells; Child; Chronic; Clinical; Clinical Trials; Collaborations; Communities; DTR gene; Data; Defense Mechanisms; Disease; Dose; Drug Kinetics; Ear; Family; Fluoroquinolones; Formulation; Functional disorder; Goals; Human; In Vitro; Infection; Infectious Agent; Innate Immune Response; Invaded; Labyrinth; Lead; Length; Medical; Metabolic; Microbial Biofilms; Modality; Modeling; Modification; Mus; N-substituted Glycines; Nitrogen; Ofloxacin; Oligonucleotides; Operative Surgical Procedures; Otitis Media; Outcome; Peptide Hydrolases; Peptides; Peptoids; Pharmaceutical Preparations; Phase; Proteolysis; Pseudomonas aeruginosa; Relapse; Resistance development; Safety; Scientist; Serial Passage; Side; Structure; Suppurative Otitis Media; Testing; Therapeutic; Time; Topical application; Toxic effect; Translations; Tympanic membrane; Variant; Vertebral column; Work; World Health; analog; antimicrobial; antimicrobial peptide; bacterial resistance; base; combat; commercialization; cost; curative treatments; design; drug development; effective therapy; hearing impairment; improved; in vivo; in vivo evaluation; infection burden; innovation; lead candidate; lead optimization; middle ear; mouse model; multidrug-resistant Pseudomonas aeruginosa; natural antimicrobial; neglected tropical diseases; novel; ototoxicity; peptidomimetics; polypeptide; pre-clinical; relative cost; screening; standard of care; success; translational medicine; treatment optimization

PROJECT SUMMARY / ABSTRACT The goal of this project is to develop a new, effective treatment for chronic suppurative otitis media (CSOM), a currently uncurable condition involving severe, chronic middle ear infection. CSOM is the most common cause of persistent hearing loss for children in the developing world, and affects 330 million people worldwide. It is characterized by a chronically infected, discharging middle ear, and currently has no effective medical therapy. The bacterium Pseudomonas aeruginosa (PA) is a leading cause of CSOM, and colonizes the middle ear via a perforated tympanic membrane, where it becomes established into a biofilm community. The current primary treatment modality for CSOM, fluoroquinolone (usually ofloxacin) eardrops, is ineffective in completely eliminating CSOM infection, apparently due to an inability to target the subpopulation of metabolically inactive bacteria within the biofilm known as ‘persister cells’. These persister cells repopulate the biofilm niche after the fluoroquinolone therapy is discontinued, causing CSOM to relapse. This interdisciplinary project leverages the combined expertise of the Santa Maria lab, which has created a mouse model for CSOM with PA biofilms and has recent middle ear translational success, and the Barron lab, which develops antimicrobials. Our innovative approach involves the design, synthesis, optimization and in vivo testing of uniquely biostable analoguesof natural antimicrobial peptides (AMPs). AMPs are natural defense mechanisms to combat infectious agents in vivo, and some are effective against biofilms; yet their poor bioavailability (i.e. rapid in vivo proteolytic degradation) limits their clinical use. We will utilize AMP mimics based which are sequence- and length-specific oligo-N-substituted glycine mimics of natural polypeptides. on peptoids, Peptoids are based on a polypeptide backbone; yet have side-chains appended to backbone nitrogens. Because of this structural difference, peptoids are completely stable to proteolysis. Furthermore, they can be made in high yields at reasonable cost, using an automated peptide synthesizer. Synthetic Antimicrobial Peptoids (SAMPs) are potent drugs that can completely eliminate persisters in biofilms. Our preliminary data show that SAMPs are more effective than ofloxacin at killing planktonic persister cells and eradicating mature biofilms. Our aims are focused on optimizing our lead SAMP candidate and confirming efficacy in our CSOM mouse model. The Aims are: (1) in vitro screening of TM5 analogs modified to improve efficacy against clinical isolate persister cells and mature biofilms and (2) showing proof of concept that the lead SAMP can be effective in a CSOM mouse model while also being non-ototoxic. After finishing our final in vivo efficacy, we plan to proceed through preclinical translation. With Phase II support, our goals will be to show non-systemic toxicity, safety, distribution, pharmacokinetics, formulation, stability, and dose escalation to assemble an IND package.

项目摘要 /摘要 该项目的目的是为慢性补充中耳炎（CSOM）开发一种新的有效治疗方法 目前，涉及严重的慢性中耳感染的无法表现的状况。 CSOM是最常见的原因 发展中国家儿童持续的听力损失，并影响全球3.3亿人。这是 以长期感染的，中耳的排出，目前没有有效的医疗疗法。 细菌铜绿假单胞菌（PA）是CSOM的主要原因，并通过 一种穿孔的鼓膜膜，在该膜中建立成生物膜群落。当前的主要 CSOM的治疗方式，氟喹诺酮（通常是氧氟沙星）耳塞，完全无效 消除CSOM感染，显然是由于无法针对代谢不活跃的亚群 生物膜中的细菌称为“持久细胞”。这些迫害细胞在 氟喹诺酮治疗被停用，导致CSOM释放。这个跨学科项目利用了 圣玛丽亚实验室的联合专业知识，该实验室创建了使用PA生物膜的CSOM鼠标模型 最近具有中耳翻译成功，而Barron Lab则开发了抗菌素。 我们的创新方法涉及独特可生物固定的设计，合成，优化和体内测试 天然抗菌胡椒（AMP）的类似物。放大器是对抗传染性的自然防御机制 体内的特工，有些是有效抗生物膜的；然而它们的生物利用度差（即体内快速蛋白水解 降解）限制了其临床用途。我们将利用基于序列和长度特异性的AMP模拟物 寡-N-溶解的天然多肽的甘氨酸模仿。在肽上，肽是基于多肽 骨干;然而，将侧链附加到骨干氮。由于这种结构差异，肽 完全稳定蛋白水解。此外，可以使用一个 自动化肽合成器。合成抗微生物肽（SAMP）是可以完全可以完全的药物 消除生物膜中的言论。我们的初步数据表明，SAMP比在 杀死浮游生物的持久细胞并根除成熟的生物膜。 我们的目标是优化我们的铅samp候选者和确认CSOM鼠标的效率 模型。目的是：（1）在体外筛选TM5类似物以提高临床分离株的效率 持久细胞和成熟的生物膜以及（2）显示概念证明，表明铅samp可以在A中有效 CSOM小鼠模型同时也是非毒性的。完成了最终的体内效率后，我们计划继续 通过临床前翻译。通过第二阶段的支持，我们的目标是显示非系统性毒性，安全性， 分布，药代动力学，配方，稳定性和剂量升级，以组装IND包装。