Structure and property driven optimization of fatty acid synthesis inhibitors for

描述（由申请人提供）：自抗生素时代开始以来，细菌对抗生素的耐药性一直是一个不断发展的问题。存在对几乎所有批准的抗生素具有抗性的革兰氏阴性菌（GNB）的分离株，并且这些病原体正在全国和地球仪中迅速传播。与此同时，新抗生素的管道几乎是空的。与革兰氏阳性菌相比，革兰氏阴性菌用额外的外双层膜保护自己。这种外膜的屏障功能依赖于脂多糖（LPS或内毒素），细胞表面上的主要脂质部分。抑制LPS合成的试剂，如酶LpxC的抑制剂，是快速杀菌的。事实上，Achaogen开发了一种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。这个研究项目导致了 ACHN-975进入临床试验的进展始于已知的LpxC抑制剂CHIR-090。Achaogen然后利用我们对药物化学规则的深入了解来合成穿过革兰氏阴性细胞膜的药物，以及我们广泛的微生物学能力来设计，合成和测试具有改进活性的新类似物。为了进一步利用LPS合成途径，我们正在研究酶AccC，也称为生物素羧化酶。这种酶催化II型脂肪酸合成的早期步骤。革兰氏阴性菌需要这种酶来合成？- LPS特有的羟基脂质。因为没有环境来源？-羟基脂肪酸（与饱和脂肪酸相反），抑制AccC将导致快速细胞死亡。来自革兰氏阴性菌的纯化AccC的抑制剂已在文献中公开，并且通过大量公开可得的共晶体结构充分理解这些化合物与酶的结合模式。然而，这些先导物对致病性GNB仅具有弱活性。我们相信，我们了解这些化合物的性质，防止其在野生型GNB中的活性。Achaogen将再次利用我们对革兰氏阴性空间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，这些抑制剂具有改进的特性，对致病性GNB更具活性。该项目的成功结果将是一系列药物样分子，它们是纯化AccC的有效抑制剂，对野生型GNB具有抗菌活性，MIC范围≤ 0.5 ug/mL。这些目标的实现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.