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: 9533994
• 负责人: Jian Li
• 金额: $ 79.38万
• 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/9533994
• 关键词: Acids; 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 infections; 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; drug candidate; drug discovery; experience; global health; improved; innovation; lead candidate; 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：世界正面临细菌出现带来的巨大且日益严重的威胁 “超级细菌”。如果细菌继续以目前的速度对多种抗生素产生耐药性 在抗生素管道继续枯竭的同时，可能会带来灾难性的成本 全球医疗保健和社会。全球多家医院爆发感染 由多重耐药 (MDR) 铜绿假单胞菌、鲍曼不动杆菌和克雷伯氏菌引起 肺炎杆菌。所有这些病原体都在 IDSA 的六种最优先危险细菌的“打击名单”上， 需要紧急关注以发现新的抗生素。多粘菌素（即多粘菌素和多粘菌素 B）用作 对于这些非常有问题的革兰氏阴性病原体引起的感染的“最后一线”治疗。很遗憾， 多粘菌素的临床应用因其肾毒性和对肺部感染的疗效不佳而受到阻碍 药代动力学限制。不幸的是，已报道质粒传播的多粘菌素耐药性 最近。从本质上讲，多粘菌素耐药性意味着完全缺乏用于治疗致命疾病的抗生素。 由这些革兰氏阴性细菌引起的感染。显然，新型抗生素的研发刻不容缓。 需要。所有这三种革兰氏阴性细菌都是该项目的重点。研究设计：建筑 根据我们过去 17 年的系统性多粘菌素药理学研究，该项目将采用我们的 合理开发新颖的构效关系（SAR）和构效关系（STR）模型 新型、更安全的多粘菌素样脂肽，针对革兰氏阴性“超级细菌”，包括多粘菌素抗性 隔离。具体目标是：（1）利用我们完善的脂肽药物化学平台 设计、合成和微生物学评估大约 300 种针对 MDR K 的新型脂肽。 肺炎杆菌、铜绿假单胞菌和鲍曼不动杆菌； (2)根据急性行为进行leawdillciamnpdriodvaete选择 有利于IND申请； (4) 培养主要候选人（和后备候选人） 基于使用啮齿动物和非动物对稳定性、毒性、PK 和 PK/PD 进行的评估 具体目标 4 的结果还将提供必要的功效和毒性数据来支持 死了。尽管这超出了本次 RFA 的范围，但我们非常热情 d 候选人将在以下机构的财政支持下参加 IND 支持的研究： 重要性：我们的创新方案将开发急需的更安全、更有效的药物 当前由革兰氏阴性“超级细菌”引起的全球健康危机。