Development of an antimicrobial peptide therapeutic for Pseudomonas infections

描述（由申请人提供）： 该申请将集中在将新型抗生素肽推进临床试验所需的关键临床前实验上。我们成功地合成了一个25个氨基酸的生物活性肽（CAP 3720 -44）的基础上的天然序列的天然宿主防御分子称为CAP 37。CAP 3720 -44和两种肽类似物CAP 3720 - 44 Ser 26和CAP 3720 -44 Ser 42对革兰氏阴性菌（包括铜绿假单胞菌和鲍曼不动杆菌）具有有效的抗微生物活性。CAP 37肽的抗生素活性的另外重要性是它们结合和中和脂多糖（LPS）或内毒素（革兰氏阴性生物体的外膜组分）的毒性作用的能力。我们假设CAP 37肽是一类新的抗生素，由于其新的抗菌活性和LPS结合活性模式，将被证明是耐药性医疗保健相关感染的有效疗法。我们的目标是开发一种新的抗生素，用于治疗急性医院环境中的严重革兰氏阴性菌感染。我们最初的适应症是用于治疗铜绿假单胞菌引起的菌血症和医院获得性肺炎。本申请的结构旨在满足向FDA成功提交研究性新药申请所需的关键里程碑。该应用程序有五个主要的研究和开发领域，包括1）先导化合物的选择，2）生产和配方，3）体外微生物学，4）先进的疾病建模研究，以确定体内疗效，以及5）药代动力学，毒理学和安全药理学。目标1：建立CAP 37肽合成的放大工艺，以确保有足够的GMP样化合物用于实验分析，并确定用于临床试验的每克规模成本的可行性。目标二：使用临床和实验室标准化研究所（CLSI）参考方法确定CAP 37肽的体外疗效和抗菌活性谱，并检查微生物通过自发和连续突变对CAP 37肽产生耐药性的倾向。目的3：确定CAP 37肽在假单胞菌肺炎和菌血症的啮齿动物和非人灵长类动物模型中的体内功效。目标4：确定肽在两种动物种属中的药代动力学，并进行所需的安全药理学和毒理学研究，以满足FDA对IND申报的要求。该应用将为治疗多种严重革兰氏阴性菌感染的新型抗生素的作用机制提供关键见解。与公共卫生的相关性。迫切需要新的抗生素来治疗与卫生保健相关的感染。病原体对当前抗生素耐药性的发生率增加导致发病率和死亡率急剧增加，这是一个严重的公共卫生问题。鉴定具有强抗微生物活性和低诱导耐药性倾向的新疗法将具有重大的公共卫生意义。

DESCRIPTION (provided by applicant): This application will focus on the critical pre-clinical experiments required to advance a novel antibiotic peptide into clinical trials. We successfully synthesized a twenty-five amino acid bioactive peptide (CAP372o-44) based on the native sequence of the natural host defense molecule known as CAP37. CAP372o-44 and two peptide analogs, CAP372o-44Ser26 and CAP372o-44 Ser42, have potent antimicrobial activity for Gram-negative bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii. Of additional importance to the antibiotic activity of CAP37 peptides, is their ability to bind and neutralize the toxic effects of lipopolysaccharide (LPS) or endotoxin, a component of the outer membrane of Gram-negative organisms. We hypothesize that CAP37 peptides are a new class of antibiotic, and due to their novel mode of antimicrobial activity and LPS binding activity, will prove to be effective therapies for drug-resistant healthcare-associated infections. Our goal is the development of a novel antibiotic for the treatment of severe Gram-negative infections in an acute hospital setting. Our initial indications are for the treatment of bacteremia and nosocomial pneumonia due to P. aeruginosa. This application is structured to satisfy the key milestones required for successful submission of an investigational new drug application to the FDA. The application has five major areas of study and development which include 1) selection of lead compound, 2) production and formulation, 3) in vitro microbiology, 4) advanced disease modeling studies to establish in vivo efficacy, and 5) pharmacokinetics, toxicology, and safety pharmacology. Aim 1: To establish the scale-up procedure of the synthesis of CAP37 peptides to ensure sufficient GMP-like compound for experimental analysis and to determine feasibility of cost per gram at scale for use in clinical trials. Aim 2: To determine the in vitro efficacy and antimicrobial spectrum of activity of the CAP37 peptides using Clinical and Laboratory Standards Institute (CLSI) reference methods and to examine the propensity for organisms to develop resistance to CAP37 peptides via spontaneous and sequential mutation. Aim 3: To determine the in vivo efficacy of CAP37 peptides in rodent and nonhuman primate models of Pseudomonas pneumonia and bacteremia. Aim 4: To determine the pharmacokinetics of the peptides in two animal species and to perform the required safety pharmacology and toxicology to meet FDA requirements for an IND submission. This application will provide key insights into the mechanism of action of a novel antibiotic for treating multiple severe Gram-negative infections. Relevance to public health. There is a critical need for new antibiotics to treat health-care associated infections. The increased incidence of pathogen resistance to current antibiotics results in dramatically increased morbidity and mortality rates, a serious public health issue. Identifying new therapeutics with strong antimicrobial activity and low propensity to induce resistance will be of great public health importance.