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

摘要 本项目的目标是研制一种广谱的替沙菌素-脂肽干粉吸入剂 旨在预防和治疗由细菌“超级细菌”引起的肺部感染的混合物。成功 任何抗生素的使用都受到来自微生物的对该化合物的潜在耐药性发展的影响。 时间是第一次使用。世界正面临着泛毒品的出现所带来的巨大和日益严重的威胁 耐药（PDR）细菌对所有可用的抗生素具有耐药性。具有1）新机制的新抗生素 2）细菌不易产生耐药性，因此迫切需要治疗肺部疾病 由PDR革兰氏阴性病原体如铜绿假单胞菌、不动杆菌 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阳性菌株 （MRSA）和肺炎链球菌（Streptococcus pneumoniae）。Teixobactin是最近发现的一种新抗生素， 新的作用机制（MOA），尽管对革兰氏阳性菌的活性谱很窄。的 teixobactin最显著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。我们已经开发出新型的替沙菌素-脂肽杂合体，其上级于天然的替沙菌素-脂肽杂合体。 因为它们保留了这种关键的抗耐药性， 对PDR革兰氏阴性菌以及PDR革兰氏阳性菌具有有效活性。我们的初步数据 显示我们的替沙菌素-脂肽杂合体作为干粉吸入剂递送显著改善了 由于其独特的MOA、无可检测的耐药性、高局部耐药性， 肺中的暴露量低，全身暴露量低，毒性低。重要的是，杂交种表现出上级 与单独化合物或每种化合物的组合治疗相比的体内功效 本质上这是该领域的一个重大进展，因为teixobactin-脂肽杂合体代表了 一流的广谱“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的国际公认记录， 药理学、抗感染干粉制剂、药代动力学/药效学和最新技术水平 抗菌剂开发设施为该项目提供了极为有力的支持。该提案将 采用一种有目的的有趣的方法来确定一个积极的主要候选人（加上一个后备） 针对PDR革兰氏阴性铜绿假单胞菌、A. baumannii和K.肺炎和革兰氏阳性 MRSA和S.用于临床前开发和IND使能研究。

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.