Elucidation of the unusual methylenomycin biosynthetic pathway in Streptomyces coelicolor

由于多重耐药病原体如万古霉素和耐甲氧西林金黄色葡萄球菌（VMRSA）的不断出现，迫切需要改进的和新的抗生素。满足这一需求的一种方法是在生产生物体中工程化天然合成（生物合成）抗生素的途径，以产生具有潜在上级性质的新型衍生物用于医学应用。抗生素生物合成途径中的基因、酶、中间体和反应的基础知识是生物合成途径工程的必要前提。亚甲基霉素属于一种不寻常的抗生素，对革兰氏阳性和革兰氏阴性细菌具有广谱活性。最近，已经鉴定了在微生物天蓝色链霉菌中组装亚甲基霉素所需的基因，并且已经表明亚甲基霉素是由分子结构单元的独特组合组装的。对生物合成基因编码的酶的分析表明，亚甲基霉素生物合成的途径是高度新颖的，并且与其他抗生素生物合成的已知途径没有相似性。本研究项目旨在通过鉴定和确定途径上中间体的分子结构并检查每个生物合成基因和酶的作用来研究独特的亚甲基霉素生物合成途径。还将探索工程化途径以产生亚甲基霉素的新型衍生物的潜力。

There is an urgent need for improved and new antibiotics due to the increasing emergence of multi-drug resistant pathogens such as vancomycin and methicillin resistant Staphylococcus aureus (VMRSA). One approach to meeting this need is the engineering of natural synthetic (biosynthetic) pathways to antibiotics in producing organisms to generate novel derivatives with potentially superior properties for medical applications. Fundamental knowledge of the genes, enzymes, intermediates and reactions involved in antibiotic biosynthetic pathways is an essential prerequisite for biosynthetic pathway engineering. Methylenomycins belong to an unusual group of antibiotics that have a broad spectrum of activity against Gram-positive and Gram-negative bacteria. Recently the genes required for assembly of the methylenomycins in the microorganism Streptomyces coelicolor have been identified and it has been shown that the methylenomycins are assembled from a unique combination of molecular building blocks. Analysis of the enzymes encoded by the biosynthetic genes indicates that the pathway for methylenomycin biosynthesis is highly novel and does not show similarities to the known pathways for biosynthesis of other antibiotics. This research project aims to investigate the unique methylenomycin biosynthetic pathway by identifying and determining the molecular structure of intermediates on the pathway and examining the role of each of the biosynthetic genes and enzymes. The potential for engineering the pathway to produce novel derivatives of the methylenomycins will also be explored.