Natural Product Derived Inhibitors of ESKAPE Pathogens

对新的有效抗生素的需求是众所周知的，不仅在科学年鉴中， 但在大众媒体上也是如此。耐药机制使许多抗生素无效，而药物 工业的发现努力已经转向更有利可图的目标。最近，疾控中心报告了一起死亡病例， 内华达州引起的肺炎克雷伯菌菌株耐药的所有26种抗生素在美国武库的潜力 然而，这些“超级细菌”仍然不寻常，后抗生素时代并没有成为定局。 结论使用具有新作用机制的新抗生素的适当管理的治疗策略 抗生素在未来的有效性。我们在这里提出一个发现计划，以确定新的 具有新作用机制的抗生素。我们的项目旨在从天然药物中发现新的抗生素。 产品，现有的抗菌药物治疗的主要来源。天然产品是一个突出的来源， 具有抗生素特性的新化学型。在1981年至2006年的25年中， 抗生素注册为天然产物或天然产物衍生物，而只有23种抗生素注册为天然产物， 发现了合成化合物。事实上，自1970年以来发现的3种新抗生素中有2种是 天然产物（达托霉素和莫匹罗星）。自然界的精致选择性和难以想象的多样性 这些产品并非偶然，它们是大自然为生存而设计的，而这些生存在很大程度上是由微生物战争驱动的。 我们的发现管道包括一类新的生物膜选择性抗生素，它们来自我们的一种天然抗生素。 产品来源，冷水海绵。Aim中这些海绵二萜的作用机制（MOA）研究 3可能提供对生物膜破坏的迫切需要的见解。该管道还包括高优先级抗生素 提取物，我们的目标是表征化学（目标1）和生物学（目标2），以确定新的天然产物 进展到MOA和相关的综合高级生物筛选（目标3）的命中数。此外，我们旨在 通过新抗生素筛选样本（目标1）的初步筛选（目标2）， 来自大部分未经研究的生物来源，包括冷水海洋无脊椎动物，海洋真菌和 放线菌，以及植物和海洋天然产物提取物的综合NCI预分级文库。 我们的项目带来了文化微型化和沉默的生物合成途径的启发创新， 最大化筛选通量，以及色谱技术，以减少在化学型重建中的努力损失。 的发现将使用临床相关ESKAPE在高通量试验中评价所有化学多样性 病原体将对命中进行细胞毒性评价，显示有利特征的命中将被推进至 全面的二次筛选。

The need for new and effective antibiotics is well known, promoted as it is, not just in the annals of science, but in the popular press as well. Resistance mechanisms have rendered many antibiotics ineffective while drug discovery efforts of the industry have turned to more profitable targets. Recently, the CDC reported a death in Nevada caused by a Klebsiella pneumonia strain resistant to all 26 antibiotics in the US arsenal of potential treatments.1 These 'superbugs' remain unusual, however, and the post-antibiotic era is not a foregone conclusion. Properly managed treatment strategies using new antibiotics with novel mechanisms of action hold the promise of antibiotic efficacy well into the future. We propose here a discovery program to identify new antibiotics with the novel mechanisms of action. Our program seeks to discover new antibiotics from natural products, the major source of existing antimicrobial therapeutics. Natural products are an outstanding source of new chemotypes bearing antibiotic properties. Consider that in the 25 years between 1981-2006, 74 new antibiotics were registered as either native natural products, or natural product derivatives, while only 23 totally synthetic compounds were discovered. Indeed, 2 of the 3 new classes of antibiotics discovered since 1970 are natural products (daptomycin and mupirocin). The exquisite selectivity and unimaginable diversity of natural products is no accident; it is designed by nature for survival purposes that are largely driven by microbial warfare. Our discovery pipeline includes a new class of biofilm-selective antibiotics derived from one of our natural product sources, a cold-water sponge. Mechanism-of-action (MOA) studies of these spongian diterpenes in Aim 3 may provide critically needed insights into biofilm disruption. The pipeline also includes high priority antibiotic extracts which we aim to characterize chemically (Aim 1) and biologically (Aim 2) to identify new natural product hits for progression to MOA and related comprehensive advanced biological screening (Aim 3). Further, we aim to keep the pipeline full through primary screening (Aim 2) of new antibiotic screening samples (Aim 1) derived from largely unstudied biological sources, including cold-water marine invertebrates, marine fungi and actinomycetes, and the comprehensive NCI pre-fractionated library of plant and marine natural product extracts. Our project brings innovation in culture miniaturization and elicitation of silent biosynthetic pathways to maximize screening throughput, and a chromatographic technique to reduce effort lost in chemotype re- discovery. All chemodiversity will be evaluated in a high-throughput assay using the clinically relevant ESKAPE pathogens. Hits will be evaluated for cytotoxicity, with those displaying favorable characteristics advancing to comprehensive secondary screening.