Biochemical and regulatory mechanisms involved in secondary metabolism and antibiotic resistance in actinobacteria

由抗生素耐药细菌引起的感染是一个主要问题，但最近出现和传播以前被认为得到控制的细菌疾病，引起了更大的担忧。克拉维酸是一种用于治疗由某些细菌引起的感染的药物，这些细菌对青霉素类抗生素具有抗药性。当克拉维酸与青霉素类抗生素联合使用时，它通过沉默抗生素的耐药机制来恢复抗生素对目标生物的作用能力。克拉维酸是由棒状链霉菌产生的，棒状链霉菌是一种与一组微生物(放线杆菌)有关的细菌，这些微生物产生许多重要的药用化合物。人们对放线杆菌产生抗生素的研究非常感兴趣，目的是找到提高抗生素产量的方法，并为新的应用寻找新的分子。用于药物配方的克拉维酸的工业生产每年价值超过10亿美元，我的工作将对确定克拉维酸在棒状链霉菌中的生产方式和控制方式至关重要。我对确定克拉维酸生物合成的关键步骤和调控机制感兴趣，目的是提高其产量。我研究的长期目标是充分了解克拉维酸的生物合成和调控，以便所获得的信息可以更广泛地应用于棒状链霉菌，为潜在的医药应用生产新的分子。我的研究计划将对学生和其他高素质人员的培训做出重大贡献，这将使加拿大受益，除了其他医学应用外，还将为发现针对抗生素耐药细菌感染的新天然产品提供熟练的个人机会。

Infections caused by antibiotic resistant bacteria are a major problem, but the recent emergence and spread of bacterial diseases previously thought to be under control is cause for even greater concern. Clavulanic acid is a drug used in the treatment of infections caused by certain bacteria that are resistant to the penicillin family of antibiotics. When clavulanic acid is given in combination with a penicillin-type antibiotic, it restores the ability of the antibiotic to act against the targeted organism by silencing its resistance mechanism. Clavulanic acid is produced by Streptomyces clavuligerus, a bacterium that is related to a group of microorganisms (the Actinobacteria) that produce many medicinally important compounds. There is great interest in studying antibiotic production by the Actinobacteria with the aim of finding ways to improve antibiotic yields and to identify new molecules for novel applications. Industrial production of clavulanic acid for use in drug formulations is valued in excess of one billion dollars annually and my work will be crucial in determining how production takes place and how it is controlled in S. clavuligerus. I am interested in identifying key steps and regulatory mechanisms involved in the biosynthesis of clavulanic acid with the aim of improving its production. The long term goal of my research is to fully understand the biosynthesis and regulation of clavulanic acid so that the information gained can be applied more broadly to S. clavuligerus to produce new molecules for potential medicinal applications. My research program will contribute significantly to the training of students and other highly qualified personnel, which will benefit Canada by providing access to individuals skilled in the discovery of new natural products for targeting antibiotic resistant bacterial infections, in addition to other medicinal applications.