Discovery of Natural Products and Natural Product-Like Inhibitors

天然产物统称为微生物、真菌和无脊椎动物生物合成的小分子，具有多种化学结构，可产生广泛的生物活性。因此，天然产物或其合成衍生物占目前临床使用的大部分治疗药物，特别是抗生素和抗肿瘤药物。随着细菌感染的发病率不断增加，其中许多是由不受标准抗生素治疗影响的细菌（所谓的耐药细菌）引起的，因此特别需要进行旨在发现和开发新型抗生素的基础和临床研究。随着海洋无脊椎动物作为天然产物来源生物的重点，我们已经确定了几种新型海洋天然产物，它们可以有效抑制野生型和耐药病原体的生长，包括耐甲氧西林金黄色葡萄球菌和耐万古霉素屎肠球菌。全细胞和体外实验表明，我们最近报道的一类抗生素通过与细菌细胞分裂机制相互作用来发挥其抗菌活性，这是抗生素发现的一个有效靶点。我们实验室正在进行的研究包括通过涉及化学合成、全细胞定位和机制研究的跨学科方法鉴定这些新型抗生素的靶点。这项研究的长期目标包括鉴定可用于治疗抗生素耐药细菌引起的细菌感染的易处理铅化合物。

Natural products, collectively known as small molecules that are biosynthesized by microorganisms, fungi and invertebrates, are engendered with diverse chemical structures that give rise to a broad range of biological activities. As such, natural products or their synthetic derivatives account for the majority of therapeutics currently in clinical use, especially among the antibiotic and antitumor drug classes. With the growing incidence of bacterial infections, many of which are caused by bacteria that are unaffected by standard antibiotic treatments (so-called drug-resistant bacteria), there is a particular need for basic and clinical research aimed at the discovery and development of new classes of antibiotics. With an emphasis on marine invertebrates as natural product source organisms, we have identified several classes of novel marine natural products that potently inhibit growth of wild type and drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Whole cell and in vitro assays have led to the hypothesis that one class of our recently reported antibiotics exerts its antibacterial activity through interactions with the bacterial cell division machinery, a validated target for antibiotic discovery. Ongoing studies in our laboratory include identification of the target/s of these novel antibiotics through an interdisciplinary approach involving chemical synthesis and whole cell localization and mechanistic studies. A long-term goal of this research includes identification of tractable lead compounds that can be used to treat bacterial infections caused by antibiotic-resistant bacteria.