Regulation of formicamycin biosynthesis: new potent antibiotics against MRSA

今天临床使用的大多数抗生素都是基于微生物天然产物，这些产物是在20世纪50年代中期抗生素发现的黄金时代发现的。值得注意的是，一种叫做链霉菌的土壤细菌占临床使用抗生素的55%。发现管道在20世纪60年代枯竭，因为科学家们开始重新发现产生相同抗生素的相同微生物菌株，并假设他们已经找到了所有这些菌株。然而，从2000年开始的基因组测序显示，这些细菌编码数千种尚未分离的新分子。新的链霉菌物种是从未开发的共生生态位中分离出来的，例如真菌生长的蚂蚁的巢穴，对其基因组进行测序，然后使用CRISPR对其进行工程改造，以激活编码新分子的生物合成基因簇。该项目的重点是分离出一种名为Streptomyces formicae的新物种，这种新物种可以制造一种名为formicamycins的新型抗生素，这种抗生素可以有效对抗多重耐药的人类病原体，如MRSA和万古霉素耐药肠球菌。该项目旨在了解甲酸霉素生物合成的调节，以期生产过量菌株，从而使分子可以进一步表征为潜在的临床先导。该项目还将确定S.并进行实验，看看这些天然的抗性基因能否赋予病原菌抗性。这对于评估这些新抗生素作为药物的潜力非常重要。

Most antibiotics in clinical use today are based on microbial natural products that were discovered during a golden age of antibiotic discovery that peaked in the mid 1950s. Remarkably, one genus of soil bacteria, called Streptomyces, account for 55% of clinically used antibiotics. The discovery pipeline dried up in the 1960s because scientists began to rediscover the same microbial strains making the same antibiotics and assumed they had found them all. However, genome sequencing from 2000 onwards has revealed these bacteria encode thousands of novel molecules that have not yet been isolated. New species of Streptomyces are isolated from under-explored, symbiotic niches such as the nests of fungus-growing ants, sequence their genomes and then engineer them using CRISPR to activate biosynthetic gene clusters encoding novel molecules. This project focusses on a new species isolated called Streptomyces formicae which makes novel antibiotics called formicamycins that are potent against multidrug resistant human pathogens such as MRSA and vancomycin resistant enterococci. The project is aimed understanding the regulation of formicamycin biosynthesis with a view to making over-producing strains so the molecules can be further characterised as potential clinical leads. The project will also determine the natural resistance mechanisms in S. formicae and do experiments to see if these natural resistance genes can confer resistance on pathogenic bacteria. This is important for assessing the potential of these new antibiotics to be used as drugs.