Structure and property driven optimization of fatty acid synthesis inhibitors for

描述(申请人提供)：自抗生素时代开始，细菌对抗生素的耐药性一直是一个不断演变的问题。存在对几乎所有经批准的抗生素都具有抗药性的革兰氏阴性细菌(GNB)菌株，这些病原体正在全国和全球迅速传播。与此同时，新抗生素的供应渠道几乎是空的。与革兰氏阳性细菌不同，革兰氏阴性细菌通过额外的外层双层膜来保护自己。这种外膜的屏障功能依赖于内毒素，这是细胞表面的主要脂类成分。抑制内毒素合成的药物，如酶抑制剂LpxC，很快就会杀菌。事实上，Achaogen已经开发出一种LpxC抑制剂ACHN-975，这是同类药物中第一个进入I期临床试验的药物。这项研究计划导致了 ACHN-975进入临床试验的进展始于一种已知的LpxC抑制剂CHIR-090。然后，Achaogen利用我们对药物化学规则的深厚知识来合成跨越两种革兰氏阴性膜的制剂，以及我们广泛的微生物学能力来设计、合成和测试具有更高活性的新类似物。为了进一步开发内毒素合成途径，我们正在研究ACCC酶，也就是生物素羧基酶。这种酶催化第二类脂肪酸合成的早期步骤。革兰氏阴性细菌需要这种酶来合成内毒素所特有的？-羟基脂。由于不存在环境来源的β-羟基脂肪酸(与饱和脂肪酸相反)，抑制ACCC将导致细胞迅速死亡。从革兰氏阴性菌中提纯的ACCC的抑制剂已经在文献中发表，这些化合物与酶的结合模式通过大量公开可用的共晶结构得到了很好的理解。然而，这些先导化合物对致病的GNB只有微弱的活性。我们相信我们了解了这些化合物的性质，这些化合物阻止了它们在野生型GNB中的活性。Achaogen将再次利用我们在革兰氏阴性领域对药物化学的深刻理解和我们的微生物学能力来设计、合成和测试新的ACCC抑制剂，这些抑制剂具有更好的性能，将更有效地对抗致病性GNB。该项目的成功成果将是一系列类药物分子，它们是纯化的ACCC的有效抑制剂，对野生型金黄色葡萄球菌具有抗菌活性，其最低抑菌浓度(≤)在0.5ug/mL范围内。实现这些目标将使我们能够启动一个全面的药物开发计划。

DESCRIPTION (provided by applicant): Bacterial resistance to antibiotics has been an evolving problem since the dawn of the antibiotics era. Isolates of Gram-negative bacteria (GNB) exist that are resistant to nearly all approved antibiotics, and these pathogens are rapidly spreading across the country and across the globe. At the same time, the pipeline of new antibiotics is nearly empty. By contrast to Gram-positive bacteria, Gram-negative organisms protect themselves with an additional outer bilayer membrane. The barrier function of this outer membrane relies on lipopolysaccharide (LPS, or endotoxin), the predominant lipid moiety on the cell surface. Agents that inhibit the synthesis of LPS, such as inhibitors of the enzyme LpxC, are rapidly bactericidal. Indeed, Achaogen has developed an LpxC inhibitor, ACHN-975, that was the first agent in its class to enter Phase I clinical trials. The research program that led to the advancement of ACHN-975 into clinical trials started with a known LpxC inhibitor, CHIR-090. Achaogen then used our deep knowledge of medicinal chemistry rules for synthesizing agents that cross both Gram-negative membranes, and our extensive microbiology capabilities to design, synthesize and test new analogs with improved activity. To further exploit the LPS synthesis pathway, we are examining the enzyme AccC otherwise known as biotin carboxylase. This enzyme catalyzes an early step in Type-II fatty-acid synthesis. Gram-negative bacteria require this enzyme to synthesize the ?-hydroxy lipids that are unique to LPS. As there are no environmental sources of ?-hydroxy fatty acids (by contrast to saturated fatty acids), inhibition of AccC will result in rapid cell death. Inhibitors of purified AccC from Gram-negative bacteria have been published in the literature, and the binding mode of these compounds to the enzyme is well understood through a large number of publicly available co-crystal structures. However, these leads are only weakly active against pathogenic GNB. We believe that we understand the properties of these compounds that prevent their activity in wild-type GNB. Achaogen will again use our deep understanding of medicinal chemistry in the Gram-negative space and our microbiology capabilities to design, synthesize and test new AccC inhibitors with improved properties that will be more active against pathogenic GNB. The successful outcome of this project will be a series of drug-like molecules that are potent inhibitors of purified AccC and have antimicrobial activity against wild-type GNB with MIC's in the range of ≤ 0.5 ug/mL. Achievement of these goals will allow us to initiate a full scale drug development program.