Novel antimicrobial agents to overcome antibiotic resistant Pseudomonas and MRSA respiratory infection

根据疾病控制和预防中心的数据，耐药感染已经与 在美国，每年有23000人死亡，200万人患病。许多死亡病例都是 与危及生命的并发症有关，尤其是败血症。对经济影响的估计各不相同，但 高达200亿美元的超额直接医疗成本和高达350亿美元的损失 住院和病假带来的生产力。不幸的是，由于一个令人担忧的问题，问题正在恶化 近年来抗药性细菌的增加以及新的抗生素的开发和发现的空白 在过去的三十年里，制药公司使用抗生素。因此，小说的发展 有效对抗抗药性细菌的疗法不仅具有科学和医学上的重要性，而且是一种 国家优先事项。我们开发了一系列合理设计的阳离子抗菌肽(ECAPs)。 使用不同的计算排列的氨基酸来实现不同药物的体外灭活- 耐药细菌菌株。其中一种先导化合物WLBU2(仅由Arg、Val和Trp制成)具有 对多种难以治疗的耐药病原体显示出强大的杀菌活性 对其他膜活性化合物产生抗药性，如天然抗菌肽(AMP) LL37和粘菌素，这是最后一种抗生素。此外，我们已经显示出显著较低的趋势 与标准抗生素和天然AMP相比，细菌对WLBU2产生抗药性。重要的是 WLBU2在铜绿假单胞菌败血症小鼠模型中显示出体内疗效 有系统地管理。由于最初的治疗指数很窄(TI≤5)，我们不断地 用系统迭代设计方法优化ECAP结构以降低寄主毒性和增强 效力和稳定性。初步数据表明，其中一些基于Trp的eCAP(统称为 W2eCAP)已经表现出更高的TI。基于这些探索性研究的令人兴奋的结果， 利用W2eCAPs克服细菌耐药性是一个吸引人的概念。因此，我们假设 W2eCAPs对DR细菌的杀菌活性增强，宿主毒性可忽略不计， 因此，可作为治疗肺炎脓毒症的有效方法。由于独特的肺 微环境，在临床使用W2eCAPs的理想之前，许多问题仍有待回答 意识到了。因此，这项建议的主要目的是了解：1)W2eCAP如何发挥其抗菌剂 在与肺部相关的条件下对主要呼吸道耐药病原体的活性 微环境；2)W2eCAPs杀菌的分子机制；(3)最佳处理 选择具有最高TI的W2eCAP的方案(全身给药与呼吸道给药相比)；以及(4) 所选W2eCAPs的药代动力学特性。

According to the Centers for Disease Control and Prevention, antibiotic-resistant infections are already linked to 23,000 deaths and 2 million illnesses in the United States each year. Many of the mortality cases are associated with life-threatening complications, especially sepsis. Estimates of the economic impact vary, but have ranged as high as $20 billion in excess direct healthcare costs, and as much as $35 billion in lost productivity from hospitalizations and sick days. Unfortunately, the problem is worsening because of an alarming increase in antibiotic-resistant bacteria in recent years and the void in the development and discovery of new antibiotics by pharmaceutical companies over the last three decades. As a consequence, development of novel therapies to effectively combat drug-resistant bacteria is not only of scientific and medical importance, but a national priority. We have developed a series of rationally engineered cationic antimicrobial peptides (eCAPs) using different amino acids computationally arranged to achieve in vitro inactivation of diverse drug- resistant bacterial strains. One of the lead compounds, WLBU2 (made only of Arg, Val, and Trp), has demonstrated potent bactericidal activity against diverse difficult-to-treat drug resistant pathogens that have developed resistance to other membrane-active compounds, such as the natural antimicrobial peptide (AMP) LL37 and colistin, an antibiotic of last resort. In addition, we have demonstrated a substantially lower tendency for bacteria to develop resistance to WLBU2 compared to standard antibiotic agents and natural AMPs. Importantly, WLBU2 demonstrates in vivo efficacy in a murine model of P. aeruginosa sepsis when the bacteria were systemically administered. Because of an initially narrow therapeutic index (TI ≤ 5), we are continuously optimizing eCAP structure using a systematic iterative design approach to lower host toxicity and enhance potency and stability. Preliminary data indicate that some of these Trp-based eCAPs (collectively referred to as W2eCAPs) have already demonstrated a higher TI. Based on the exciting results from these exploratory studies, the use of W2eCAPs to overcome bacterial resistance is an appealing concept. Hence, we hypothesize that W2eCAPs will display enhanced bactericidal activities against DR bacteria as well as negligible host toxicity and, therefore, can be used as an effective therapy to treat pneumonia-induced sepsis. Due to the unique lung microenvironment, many questions remain to be answered before the clinical ideal of using W2eCAPs can be realized. Thus, the primary purpose of this proposal is to understand: 1) how W2eCAPs exert their antimicrobial activities against major respiratory drug resistant pathogens in conditions associated with the lung microenvironment; 2) the molecular mechanisms used by W2eCAPs to kill bacteria; (3) the optimal treatment regimens (systemic compared to airway delivery) to select the W2eCAP with the highest TI; and (4) the pharmacokinetic properties of the selected W2eCAPs.