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

由抗生素耐药性细菌引起的感染是一个主要问题，但最近出现和传播的细菌性疾病，以前认为是在控制之下，是引起更大的关注。克拉维酸是一种用于治疗某些细菌引起的感染的药物，这些细菌对青霉素家族的抗生素具有耐药性。当克拉维酸与青霉素类抗生素联合给药时，它通过沉默其耐药机制来恢复抗生素对靶生物的作用能力。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（放线菌）有关的细菌，可产生许多药用重要化合物。人们对研究放线菌的抗生素生产有很大的兴趣，目的是找到提高抗生素产量的方法和鉴定用于新应用的新分子。用于药物制剂的克拉维酸的工业生产每年价值超过10亿美元，我的工作对于确定如何生产以及如何控制S。棒形的我感兴趣的是确定克拉维酸生物合成中的关键步骤和调控机制，以提高其产量。本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S。clavuligerus生产新的分子用于潜在的医药应用。我的研究计划将大大有助于培养学生和其他高素质的人才，这将有利于加拿大提供机会，在新的天然产品的发现，针对抗生素耐药性细菌感染，除了其他医药应用熟练的个人。

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.