Natural Product Derived Inhibitors of ESKAPE Pathogens

对新的有效抗生素的需求是众所周知的，正如它所提倡的那样，不仅仅是在科学编年史上， 但在大众媒体上也是如此。耐药性机制使许多抗生素在服用药物时无效 该行业的发现努力已转向更有利可图的目标。最近，疾控中心报告了一起死亡事件 内华达州肺炎克雷伯氏菌菌株对美国潜在的所有26种抗生素产生抗药性 治疗方法1.然而，这些“超级细菌”仍然不同寻常，抗生素后时代并不是必然的 结论。使用具有新作用机制的新抗生素的适当管理治疗策略 抗生素疗效的承诺在很长一段时间内。我们在这里提出了一个发现计划，以确定新的 具有新作用机制的抗生素。我们的计划寻求从天然药物中发现新的抗生素 产品，现有抗菌疗法的主要来源。天然产品是一种突出的 具有抗生素特性的新化学类型。考虑到在1981-2006年间的25年间，74个新的 抗生素被注册为天然产品或天然产品衍生品，而总共只有23种 合成化合物被发现。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)。自然界精致的选择性和难以想象的多样性 产品不是偶然的；它是为在很大程度上由微生物战争驱动的生存目的而设计的。 我们的发现计划中包括一种新的生物被膜选择性抗生素，来自我们天然的一种 产品来源：冷水海绵。海绵二萜类化合物在AIM中的作用机理研究 3可能为生物膜破坏提供急需的见解。该流水线还包括高优先级的抗生素 我们的目标是对提取物进行化学(目标1)和生物学(目标2)表征，以确定新的天然产物 进展到MOA和相关的全面高级生物筛查的命中率(目标3)。此外，我们的目标是 通过新的抗生素筛选样品(目标1)的初步筛选(目标2)保持流水线满 来自大部分未被研究的生物来源，包括冷水海洋无脊椎动物、海洋真菌和 放线菌，以及全面的NCI植物和海洋天然产品提取物预分级库。 我们的项目带来了培养微型化的创新和无声生物合成途径的启发 最大限度地提高筛选吞吐量，以及一种减少化学型重新鉴定工作损失的层析技术 发现号。所有的化学多样性将在高通量分析中使用临床相关的ESKAPE进行评估 病原体。将对HITS进行细胞毒性评估，那些表现出良好特征的HITS将进入 全面二次筛查。

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.