Discovery of Natural Products and Natural Product-Like Inhibitors

天然产物--主要由微生物、真菌和无脊椎动物生物合成的小分子--具有不同的化学结构，从而产生广泛的生物活性。因此，目前使用的治疗药物主要是天然产物或其合成衍生物，尤其是在抗生素和抗肿瘤药物中。以海洋无脊椎动物为重点，我们在上一个资助期内发现了几类能有效抑制野生和抗药性病原体生长的新型海洋天然产品，包括耐甲氧西林金黄色葡萄球菌和抗万古霉素粪肠球菌。全细胞和体外试验已经导致了一种假设，即一类抗生素通过与细菌细胞分裂机制的不明相互作用来发挥其抗菌活性。以细菌细胞分裂为目标发现新的抗生素最近得到了验证。我们实验室正在进行的研究包括通过跨学科的方法确定这些新型抗生素的靶点/S，涉及化学合成、全细胞定位和机制研究。

Natural products - small molecules biosynthesized primarily 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 currently used therapeutics, especially among antibiotics and antitumor agents. With an emphasis on marine invertebrates, we have identified during the last funding period 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 antibiotics exerts its antibacterial activity through unidentified interactions with the bacterial cell division machinery. Targeting bacterial cell division for the discovery of new antibiotics has recently been validated. 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.