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 该项目的目的是开发广谱的干粉吸入teixobactin-lipopeptide 杂种旨在预防和治疗由细菌“超级细菌”引起的肺部感染。成功 使用任何抗生素的使用受到对这种化合物的潜在发展的损害 时间首先使用。世界正面临着泛滥的巨大威胁 对所有可用抗生素抗性的抗性（PDR）细菌。带有1）新机制的新抗生素 动作和2）迫切需要细菌无法轻易产生抗性以治疗肺 由PDR革兰氏阴性病原体（如铜绿假单胞菌），阿纳门杆菌引起的感染 Baumannii和Klebsiella肺炎和革兰氏阳性耐甲氧西林金黄色葡萄球菌的菌株 （MRSA）和肺炎链球菌。 Teixobactin是一种最近发现的新抗生素，具有 新型作用机理（MOA），尽管是针对革兰氏阳性细菌的狭窄活性。这 Teixobactin最著名的特性是它是细菌无法轻易发展的第一个也是唯一的抗生素 抵抗。我们已经开发了新型的Teixobactin-脂肽杂种，它们优于天然 Teixobactin保留了此关键的抗耐药性，此外，具有更广泛的光谱， 具有针对PDR革兰氏剂 - 阴性的有效活性以及PDR革兰氏酶。我们的初步数据 表明我们作为干粉吸入的Teixobactin-lipopeptide杂种已显着改善 通过其独特的MOA治疗肺部感染的功效，没有可检测的抗性，高局部 肺部暴露低且毒性低的肺暴露。重要的是，杂种表现出了优越 与各个化合物的组合治疗相比，体内功效或每种化合物的组合 本身。这是该领域的重大发展，因为Teixobactin-lipopeptide hybrid代表 第一类宽光谱“防抗性”干粉抗生素用于治疗 PDR细菌肺部感染。我们国际公认的抗生素发现记录， 药理学，抗感染干粉配方，药代动力学/药效学和最先进的 抗菌开发的设施为该项目提供了极大的支持。提案将 采用专门设计的漏斗方法来识别活跃的主要候选人（加上一个备用） 针对铜绿假单胞菌，A。Baumannii和K.肺炎的PDR革兰氏ram阴性菌株和革兰氏阳性 MRSA和肺炎链球菌的菌株用于临床前发育和辅助研究。