Development of a broad spectrum teixobactin-lipopeptide hybrid for the treatment of lung infections caused by pan-drug resistant ‘superbugs’

开发广谱替克菌素-脂肽杂合体，用于治疗泛耐药“超级细菌”引起的肺部感染

• 批准号: 10503471
• 负责人: Gauri G Rao
• 金额: $ 67.61万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-21 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503471
• 关键词: Acinetobacter baumannii; Address; Animal Model; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Back; Bacteria; Cavia; Chemistry; Clinical; Dangerousness; Data; Development; Disease Outbreaks; Drug Exposure; Drug Kinetics; Drug resistance; Engineering; Evaluation; Formulation; Future; Goals; Gram-Positive Bacteria; Grant; Healthcare; Hospitals; Human; Hybrids; In Vitro; Individual; Infection; Inhalation; International; Klebsiella pneumoniae; Laboratories; Lung; Lung infections; Medical; Medicine; Microbiology; Minimum Inhibitory Concentration measurement; Modeling; Modern Medicine; Non-Rodent Model; Outcome; Patients; Pharmaceutical Chemistry; Pharmacodynamics; Pharmacology; Powder dose form; Property; Pseudomonas aeruginosa; Race; Rattus; Records; Regimen; Reporting; Resistance; Resistance development; Rodent; Site; Societies; Staphylococcus aureus; Streptococcus pneumoniae; Superbug; System; Techniques; Therapeutic; Time; Toxic effect; Treatment Efficacy; acute toxicity; analog; antimicrobial; bacterial resistance; base; candidate selection; comparative efficacy; cost; design; dosage; drug resistant bacteria; economic value; efficacy study; experience; imaging approach; imaging system; improved; in vivo; innovation; interdisciplinary approach; lead candidate; methicillin resistant Staphylococcus aureus; non-Native; novel; novel antibiotic class; parenteral administration; particle; pathogen; pharmacokinetics and pharmacodynamics; preclinical development; prevent; resistant strain; systemic toxicity; therapeutic development

ABSTRACT The goal of this project is to develop a broad-spectrum dry powder inhalation teixobactin-lipopeptide hybrid aimed at preventing and treating lung infections caused by bacterial `superbugs'. The successful use of any antibiotic is compromised by the potential development of resistance to that compound from the time it is first used. The world is facing an enormous and growing threat from the emergence of pan-drug resistant (PDR) bacteria that are resistant to all available antibiotics. New antibiotics with 1) novel mechanisms of action and 2) against which bacteria cannot easily develop resistance are urgently needed to treat lung infections caused by the PDR Gram-negative pathogens like Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae and Gram-positive strains of methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae. Teixobactin is a recently discovered new antibiotic that possesses a novel mechanism of action (MOA), albeit, a narrow spectrum of activity against Gram-positive bacteria. The most notable property of teixobactin is that it is the first and only antibiotic that bacteria cannot easily develop resistance against. We have developed novel teixobactin-lipopeptide hybrids that are superior to native teixobactin as they retain this key anti-resistance property and in addition have a broader-spectrum, with potent activity against PDR Gram-negatives, as well as PDR Gram-positives. Our preliminary data show that our teixobactin-lipopeptide hybrids delivered as a dry powder inhalation have significantly improved efficacy for the treatment of lung infections by virtue of their unique MOA, no detectable resistance, high local exposure in the lungs with low systemic exposure and low toxicity. Importantly, the hybrids displayed superior in vivo efficacy compared to treatment with the combination of the individual compounds or each compound per se. This is a significant development in the field as the teixobactin-lipopeptide hybrid represents the first-in class broad-spectrum `resistance-proof' dry powder inhalation antibiotic for the treatment of PDR bacterial lung infections. Our internationally recognized track records in antibiotic discovery, pharmacology, anti-infective dry powder formulation, pharmacokinetics/pharmacodynamics and state-of-the-art facilities for antimicrobial development provide extremely strong support for this project. The proposal will employ a purpose designed funneling approach to identify a lead candidate (plus one back-up) that is active against PDR Gram-negative strains of P. aeruginosa, A. baumannii and K. pneumoniae and Gram-positive strains of MRSA and S. pneumoniae for preclinical development and IND-enabling studies.

抽象的 该项目的目标是开发广谱干粉吸入替克巴汀脂肽 旨在预防和治疗细菌“超级细菌”引起的肺部感染的混合药物。成功者 任何抗生素的使用都会受到对该化合物潜在的耐药性的影响 第一次使用的时间。世界正面临泛毒品的出现带来的巨大且日益严重的威胁 对所有可用抗生素具有耐药性的耐药 (PDR) 细菌。具有 1) 新机制的新型抗生素 2) 肺部治疗迫切需要细菌不易产生耐药性的药物 由 PDR 革兰氏阴性病原体（如铜绿假单胞菌、不动杆菌）引起的感染 鲍曼不动杆菌和肺炎克雷伯菌以及耐甲氧西林金黄色葡萄球菌的革兰氏阳性菌株 (MRSA) 和肺炎链球菌。 Teixobactin 是最近发现的一种新型抗生素，具有 新的作用机制（MOA），尽管针对革兰氏阳性菌的活性范围较窄。这 teixobactin 最显着的特性是它是第一种也是唯一一种细菌不易产生的抗生素 抵抗。我们开发了新型 teixobactin-脂肽杂合体，其性能优于天然产物 teixobactin，因为它们保留了这种关键的抗耐药性特性，此外还具有更广泛的谱， 对 PDR 革兰氏阴性菌和 PDR 革兰氏阳性菌具有有效活性。我们的初步数据 结果表明，我们的 teixobactin-脂肽杂合剂以干粉吸入形式提供时已显着改善 凭借其独特的 MOA、无可检测到的耐药性、高局部 肺部暴露，全身暴露低，毒性低。重要的是，混合动力车表现出优越的性能 与单独化合物或每种化合物的组合治疗相比的体内功效 本身。这是该领域的一项重大进展，因为 teixobactin-脂肽杂合体代表了 一流的广谱“抗耐药性”干粉吸入抗生素，用于治疗 PDR 细菌性肺部感染。我们在抗生素发现方面取得了国际公认的业绩记录， 药理学、抗感染干粉制剂、药代动力学/药效学和最新技术 抗菌药物开发设施为本项目提供了极其有力的支持。该提案将 采用专门设计的漏斗方法来确定活跃的主要候选人（加上一名后备候选人） 针对铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌的 PDR 革兰氏阴性菌株以及革兰氏阳性菌株 MRSA 和肺炎链球菌菌株用于临床前开发和 IND 启用研究。