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

抗生素耐药细菌引起的感染是一个主要问题，但以前认为已得到控制的细菌性疾病最近的出现和传播引起了更大的关注。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耐药性。当克拉维酸与青霉素类抗生素联合使用时，它通过沉默其耐药机制来恢复抗生素对目标生物的作用能力。Clavulanic acid Clavulanic acid clavuligerus链霉菌clavuligerus链霉菌clavuligerus链霉菌是一种与一组微生物（放线菌）有关的细菌，放线菌可以产生许多重要的药用化合物。人们对放线菌生产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，并为新的应用发现新分子。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，我的工作对于确定如何在S. clavuligerus中进行生产以及如何控制生产至关重要。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。我的长期研究目标是充分了解clavulanic酸的生物合成和调控，以便将所获得的信息更广泛地应用于S. clavuligerus，以产生具有潜在药用价值的新分子。我的研究项目将为培养学生和其他高素质人才做出重大贡献，这将使加拿大受益，因为它将为发现针对抗生素耐药细菌感染的新天然产物以及其他医学应用提供技术人员。

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.