Elucidation of the unusual methylenomycin biosynthetic pathway in Streptomyces coelicolor

由于耐万古霉素和耐甲氧西林金黄色葡萄球菌(VMRSA)等多重耐药病原体的出现，迫切需要改进和新的抗生素。满足这一需求的一种方法是设计天然合成(生物合成)途径来生产生物体中的抗生素，以产生具有潜在更好的医疗应用性能的新的衍生物。了解抗生素生物合成途径中涉及的基因、酶、中间体和反应的基础知识是生物合成途径工程的基本前提。甲氧西林属于一组不寻常的抗生素，对革兰氏阳性和革兰氏阴性细菌具有广泛的活性。最近，在微生物天蓝色链霉菌中组装亚甲氧菌素所需的基因已经被鉴定，并且已经证明亚甲氧菌素是由一种独特的分子构件组合组装而成的。对生物合成基因所编码的酶的分析表明，甲氧霉素的生物合成途径是高度新颖的，与已知的其他抗生素的生物合成途径并不相似。本研究旨在通过鉴定和确定中间产物的分子结构，并研究每一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。还将探索设计该途径以生产新型亚甲氧菌素衍生物的可能性。

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.