Targeting the Urgent Need for New Antibiotics against Gram-negative ‘Superbugs’

针对针对革兰氏阴性“超级细菌”的新型抗生素的迫切需求

• 批准号: 9361074
• 负责人: Jian Li
• 金额: $ 105.98万
• 依托单位: MONASH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9361074
• 关键词: Acinetobacter baumannii; Acute; Advanced Development; Agreement; Americas; Amino Acids; Animal Model; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Attention; Australia; Back; Bacteria; Biology; Centers for Disease Control and Prevention (U.S.); Chemicals; Clinic; Clinical; Colistin; Combating Antibiotic Resistant Bacteria; Communicable Diseases; Country; Dangerousness; Data; Development; Disease Outbreaks; Drug Kinetics; Evaluation; Financial Support; Gram-Negative Bacteria; Healthcare; Hospitals; Human; Incidence; Infection; International; Klebsiella pneumonia bacterium; Lead; Licensing; Life; Lung; Mediation; Medical; Medicine; Microbiology; Modeling; Modification; Multi-Drug Resistance; National Institute of Allergy and Infectious Disease; Non-Rodent Model; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Physicians; Plasmids; Polymyxin B; Polymyxin Resistance; Polymyxins; Positioning Attribute; Property; Pseudomonas aeruginosa; Reporting; Research; Research Design; Research Proposals; Resistance development; Rodent; Safety; Series; Societies; Structure; Structure-Activity Relationship; Superbug; System; Therapeutic; Time; Toxic effect; Translations; Universities; acute toxicity; bacterial resistance; base; candidate selection; combat; cost; design; disorder prevention; drug candidate; drug discovery; experience; global health; improved; innovation; multidrug-resistant Pseudomonas aeruginosa; nephrotoxicity; novel; novel therapeutics; pathogen; preclinical development; programs; virtual

Background: The world is facing an enormous and growing threat from the emergence of bacterial `superbugs'. If bacteria continue developing resistance to multiple antibiotics at the present rate and at the same time the antibiotic pipeline continues to dry up, there could be catastrophic costs to healthcare and society globally. Numerous hospitals worldwide have experienced outbreaks of infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. All of these pathogens are on the IDSA `hit list' of the six top-priority dangerous bacteria that require urgent attention to discover new antibiotics. Polymyxins (i.e. colistin and polymyxin B) are used as the `last-line' of therapy for infections caused by these very problematic Gram-negative pathogens. Unfortunately, the clinical utility of polymyxins is hindered by their nephrotoxicity and poor efficacy against lung infections due to pharmacokinetic limitations. Unfortunately, plasmid-borne resistance to polymyxins has been reported recently. In essence, polymyxin resistance implies a total lack of antibiotics for treatment of deadly infections caused by these Gram-negative bacteria. Clearly, the development of new antibiotics is urgently needed. All three of these Gram-negative bacteria are the focus of this project. Research Design: Building upon our systematic polymyxin pharmacology research over the last 17 years, this project will employ our novel structure-activity relationship (SAR) and structure-toxicity relationship (STR) models to rationally develop novel, safer polymyxin-like lipopeptides that target Gram-negative `superbugs' including polymyxin-resistant isolates. The Specific Aims are: (1) To employ our well established lipopeptide medicinal chemistry platform to design, synthesize and microbiologically evaluate approximately 300 novel lipopeptides against MDR K. pneumoniae, P. aeruginosa and A. baumannii; (2) To conduct leawdillciamnpdriodvaete selection based upon acute conduc nd benefit the IND application; and (4) To develop the lead candidate (and a back-up) s based upon evaluations of the stability, toxicity, PK and PK/PD using rodent and non- ults from Specific Aim 4 will also provide essential efficacy and toxicity data to support dies. Even though it is beyond the scope of this RFA, we are very enthusiastic d candidate will be taken into IND-enabling studies with financial support from ificance: Our innovative proposal will develop much-needed safer and more efficacious t the current global health crisis caused by Gram-negative `superbugs'.

背景：由于细菌的出现，世界正面临着巨大的威胁 “超级细菌”。如果细菌继续以目前的速率和AT产生对多种抗生素的抗性 同时，抗生素管道继续干燥，可能会有灾难性的成本 全球医疗保健和社会。全球许多医院经历了感染的爆发 由抗多药（MDR）铜绿假单胞菌，鲍曼尼杆菌和克雷伯氏菌引起的 肺炎。所有这些病原体都在IDSA的“命中列表”中 需要紧急注意才能发现新的抗生素。多霉菌素（即结肠菌素和多粘蛋白B）用作 这些非常有问题的革兰氏阴性病原体引起的感染的治疗的“最后一线”。很遗憾， 肾毒性的肾毒性和对肺部感染的疗效不佳，造成多霉菌素的临床实用性受到阻碍 到药代动力学的局限性。不幸的是，据报道质粒传播对多碳素的抗性 最近。本质上，多牙剂抗性意味着完全缺乏治疗致命的抗生素 这些革兰氏阴性细菌引起的感染。显然，新抗生素的开发是迫切的 需要。所有这三个革兰氏阴性细菌都是该项目的重点。研究设计：建筑物 在过去的17年中，在我们系统的多氧化剂药理学研究中，该项目将采用我们的 新颖的结构活性关系（SAR）和结构毒性关系（STR）模型合理发展 靶向革兰氏阴性“超级细菌”，包括抗多氧蛋白的新颖，更安全的多肽类脂蛋白 分离物。具体目的是：（1）使用我们建立的脂肽药物化学平台 设计，合成和微生物学评估了大约300种针对MDR K的新型脂肽。 Pneumoniae，P。eruginosa和A. Baumannii； （2）基于急性螺旋，进行Leawdillciamnpdriodvaete选择 nd受益于IND申请； （4）发展主要候选人（和备份） s基于对稳定性，毒性，PK和PK/PD的评估 特定AIM 4的Ults还将提供基本功效和毒性数据以支持 死亡。即使它超出了此RFA的范围，我们也非常热情 D候选人将在经济支持的情况下将 IFICANCE：我们的创新提议将发展出急需的更安全，更有效的 t当前由革兰氏阴性“超级细菌”造成的全球健康危机。