Optimization of Neoglycoside Antibiotics for Nosocomial Pathogens and Select Agen

描述(申请人提供)：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。对于生物体来说，没有有效的抗生素并不少见，本质上是让我们回到了抗生素出现之前的时代。耐药性也被定义在选择药物中，例如马达加斯加的鼠疫耶尔森氏菌对氨基糖苷的耐药性。Achaogen已经开发了几个新的氨基糖苷类抗生素(新糖苷类)。这些药物显著提高了对多种多重耐药的革兰氏阴性杆菌和耐甲氧西林金黄色葡萄球菌(MRSA)的活性。在不同的系列中，先导化合物已被鉴定为对铜绿假单胞菌和不动杆菌有很强的活性。这项提案的目的是在提案的整个范围内检查最多五个此类分子，对它们进行排序，并对至少两个分子进行进展，使其应用于新药。氨基糖苷类药物由于耐药性的增加和潜在的肾毒性，已经越来越少被使用。这些新糖苷消除了许多与耐药性有关的问题。在特定的目标#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。我们可以确定暴露的目标，这将导致最佳的细菌细胞杀灭和抑制耐药细菌亚群。这些目标将通过应用创新的大型数学混合模型来确定。在特定的目标2中，我们将使用两个动物模型来验证这些暴露目标。由于鼠和人的半衰期不同，我们将在所有动物模型中使用一种新的方法来“人性化”给药。其中包括革兰氏阴性肺炎的小鼠模型和小鼠大腿感染作为皮肤/皮肤结构感染的替代品。后一种模式将在中性粒细胞减少和正常情况下运行。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的原因。我们将通过了解粒细胞的影响来验证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，允许生成任何氨基/新糖苷类药物的浓度-时间曲线，以模拟人类尿路曲线。通过量化hPRTE细胞内随时间变化的药物数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。暴露与影响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(最大效果/最小毒性)。在具体目标#4中，我们将使用人口PK建模和蒙特卡洛模拟来确定最优药物剂量。我们的目标是将至少2个分子带到NDA，并提供最佳剂量/持续时间的治疗。多重耐药细菌已经成为医院获得性感染患者的一个巨大问题。我们打算优化新的氨基糖苷类抗生素(新糖苷类)的开发，以满足这一需求，并为鼠疫、炭疽以及马来伯克霍尔德氏菌和假鼻疽等病原体的治疗提供新产品。我们打算确定一种具有非常广泛的光谱的药物来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。它们特别耐药，因此在ICU环境下的严重感染患者中很难治疗，本提案的目的是找出一种专门针对后一种病原体具有极强活性的制剂。

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.