Optimization of Neoglycoside Antibiotics for Nosocomial Pathogens and Select Agen

描述（由申请方提供）：革兰氏阴性菌的多重耐药性是ICU环境中感染患者的常见问题。铜绿假单胞菌和不动杆菌属。没有对该生物体有活性的抗生素并不罕见，这基本上使我们回到了前抗生素时代。耐药性也已在Select Agents中定义，例如马达加斯加鼠疫耶尔森氏菌的氨基糖苷类耐药性。Achaogen开发了几个系列的新氨基糖苷类抗生素（新糖苷类）。这些药物对多种多重耐药革兰氏阴性杆菌和耐甲氧西林金黄色葡萄球菌（MRSA）具有显著改善的活性。在不同的系列中，已经鉴定出先导化合物对铜绿假单胞菌和不动杆菌属具有有效活性。本提案的目的是在提案的范围内检查最多五种分子，对它们进行排序，并对至少两种分子进行新药申请。氨基糖苷类药物由于耐药性增加和可能引起肾毒性而较少使用。这些新糖苷类克服了大量与耐药性相关的问题。在具体目标#1中，我们将使用我们的中空纤维感染模型来研究候选分子。我们可以确定暴露目标，这将导致最佳的细菌细胞杀灭和耐药细菌亚群的抑制。这些目标将通过应用创新的大型数学混合模型来确定。在具体目标2中，我们将使用两种动物模型来验证这些暴露目标。由于小鼠和人的半衰期之间的差异，我们将采用一种新的方法，“人性化”的药物管理在所有的动物模型。这些包括革兰氏阴性肺炎的鼠模型和作为皮肤/皮肤结构感染的替代物的小鼠大腿感染。后一种模型将在正常和非正常条件下运行。我们将对所有数据应用另一个全新的模型，以了解粒细胞杀死病原体。我们将通过了解粒细胞影响来确认SA #1的暴露目标。在具体目标#3中，我们开发了一种全新的人近端肾小管上皮细胞（hPRTE细胞）体外系统，可生成模拟人尿路特征的任何氨基/新糖苷类药物的浓度-时间曲线。通过随时间定量hPRTE细胞内的药物量并观察细胞凋亡或坏死，我们可以得出药物暴露、持续时间和肾毒性事件发生之间的关系。暴露与效应和毒性之间的关系允许探索剂量和持续时间，以同时优化这些关系（最大效应/最小毒性）。在具体目标4中，我们将采用群体PK建模和Monte Carlo模拟来确定最佳药物剂量。我们的目标是以最佳剂量/治疗持续时间使至少2个分子进入NDA。多重耐药微生物已成为医院获得性感染患者的一个巨大问题。我们打算优化新氨基糖苷类抗生素（新糖苷类）的开发，以满足这一需求，并提供用于治疗特定病原体（如鼠疫、炭疽）和病原体（如鼻疽伯克霍尔德氏菌和类鼻疽）的新产品。我们打算确定一种具有非常广谱的病原体，以解决与许多这些病原体相关的感染问题。然而，由于铜绿假单胞菌和不动杆菌属。特别耐药，因此难以在ICU环境中治疗严重感染的患者，本发明的目的是鉴定一种针对这些后者病原体的极其有效的活性而特别优化的试剂。

DESCRIPTION (provided by applicant): Multi-drug resistance in Gram-negative bacteria is a common problem in infected patients in the ICU environment. With Pseudomonas aeruginosa and Acinetobacter spp. it is not an uncommon event for there to be no antibiotics active for the organism, essentially returning us to the pre-antibiotic era. Resistance has also been defined in Select Agents, such as aminoglycoside resistance in Yersinia pestis in Madagascar. Achaogen has developed several series of new aminoglycoside antibiotics (neoglycosides). These agents have markedly improved activity against a wide variety of multi-resistant Gram-negative bacilli and also against Methicillin-Resistant Staphylococcus aureus (MRSA). In a different series, lead compounds have been identified with potent activity against Pseudomonas aeruginosa and Acinetobacter spp. It is the intent of this proposal to examine up to five of these molecules over the span of the proposal, rank order them and, for at least two of the molecules, to progress them into New Drug Applications. Aminoglycosides have become less used because of increasing resistance and their potential to cause nephrotoxicity. These neoglycosides obviate a great deal of the problems associated with resistance. In Specific Aim #1, we will employ our hollow fiber infection model to study candidate molecules. We can identify exposure targets that will result in optimal bacterial cell kill and suppression of resistant bacterial subpopulations. These targets will be identified through application of innovative large mathematical mixture models. In Specific Aim # 2, we will employ two animal models to validate these exposure targets. Because of the difference between murine and human half lives, we will employ a novel method of "humanizing" the drug administration in all animal models. These include a murine model of Gram-negative pneumonia and mouse thigh infection as a surrogate for skin/skin structure infection. This latter model will be run in both neutropenic and normal conditions. We will apply another completely novel model to all data, to understand pathogen kill by granulocytes. We will validate exposure targets from SA #1 with an understanding of the granulocyte impact. In Specific Aim #3, we developed a completely novel in vitro system with human proximal renal tubular epithelial cells (hPRTE cells) allowing generation of a concentration-time profile for any amino/neoglycoside that mimics the human urinary tract profile. By quantifying the amount of drug inside hPRTE cells over time and observing for apoptosis or necrosis, we can derive a relationship between drug exposure, duration and nephrotoxic event occurrence. Relationships between exposure and both effect and toxicity allows exploration of doses and durations to optimize these relationships simultaneously (maximal effect/ minimal toxicity). In Specific Aim # 4, we will employ population PK modeling with Monte Carlo simulation to identify optimal drug doses. Our aim is to bring at least 2 molecules to NDA with optimal doses/durations of therapy. Multi-resistant organisms have become a huge problem in patients with hospital-acquired infections. We intend to optimize the development of new aminoglycoside antibiotics (neoglycosides) to address this need and also to provide new products for the therapy of Select Agents, such as Plague, Anthrax and pathogens such as Burkholderia mallei and pseudomallei. We intend to identify an agent with very broad spectrum to address the infection problems associated with many of these pathogens. However, because Pseudomonas aeruginosa and Acinetobacter spp. are especially resistant and, hence, difficult to treat in seriously infected patients in the ICU setting, it is an aim of this proposal to identify an agent that is specifically optimized for extremely potent activity against these latter pathogens.