Regulation and biosynthesis of bioactive secondary metabolites in Streptomyces clavuligerus and other related Streptomyces species

抗生素耐药细菌的出现和传播引起了人们对我们治疗由它们引起的感染的能力的许多担忧。这为发现新抗生素和制定治疗此类感染的策略的研究注入了新的活力。对抗细菌病原体的一些最佳解决方案以天然产物的形式来自大自然，其中也包括其他细菌产生的化合物。这些化合物中的大多数是通过特定的途径和基因组合合成的，这些基因大多存在于某些微生物群中。-内酰胺家族的天然产物包括青霉素和头孢菌素抗生素等成员，它们在人类使用中有着悠久的历史。它们也是使用最广泛的一类抗生素，但-内酰胺耐药性一直是一个挑战。某些酶可以化学灭活青霉素和头孢菌素类抗生素，从而引起耐药性。Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid Clavulanic acid棒草酸在工业上是用棒草链霉菌生产的。导致克拉维酸产生的生物合成途径仅部分为人所知，并且有关该过程中涉及的所有基因的细节也缺乏。众所周知，链霉菌可以产生许多重要的药用化合物，研究它们的目的是找到提高天然产物产量和识别新分子的方法，这是很有兴趣的。在过去的二十年里，人们已经发现链霉菌含有可能产生许多天然产物的预测基因，但只有少数是在实验室条件下生产的。因此，这些所谓的“未知或神秘”天然产物可能是未来人类和兽医用药的来源。我的长期工作目标是充分了解S. clavuligerus和相关细菌中clavulanic酸和其他天然产物生物合成的控制机制。这一研究项目将在知识的产生方面做出重大贡献，这些知识可用于生产用于新应用的分子。此外，它将培养学生和其他高素质的人员，这将使加拿大受益，因为它为发现和分析天然产品的个人提供了机会。

The emergence and spread of antibiotic resistant bacteria has raised many concerns regarding our ability to treat infections caused by them. This has reinvigorated research into the discovery of new antibiotics and for devising strategies to treat such infections. Some of the best solutions for combating bacterial pathogens come from nature in the form of natural products, which also include chemical compounds produced by other bacteria. Most of these compounds are synthesized using specialized pathways and sets of genes, which are mostly present is certain groups of microorganisms. The -lactam family of natural products includes members such as the penicillin and cephalosporin antibiotics, which have a long history of human use. They are also the most widely used class of antibiotics, but -lactam resistance has always posed a challenge. Certain enzymes can chemically inactivate penicillin and cephalosporin antibiotics to cause resistance. Clavulanic acid is a naturally produced inhibitor of such enzymes, and when used in combination with a penicillin-type antibiotic, it restores the ability of the antibiotic to act against the otherwise resistant pathogen. Clavulanic acid is industrially produced using the bacterium Streptomyces clavuligerus. The biosynthetic pathway leading to clavulanic acid production is only partially known, and details regarding all of the genes involved in the process are also lacking. The Streptomyces are known to produce many medicinally important compounds and there is great interest in studying them with the aim of finding ways to improve natural product yields and to identify new molecules. Within the last two decades it has been found that the Streptomyces contain predicted genes for potentially making many natural products, but only a few are produced under laboratory conditions. Therefore, these so called "unknown or cryptic" natural products could be sources of future drugs for human and veterinary use. The long term goal of my work is to fully understand the mechanisms controlling the biosynthesis of clavulanic acid and other natural products in S. clavuligerus and related bacteria. This research program will contribute significantly in the generation of knowledge that can be used to produce molecules for novel applications. In addition, it will train students and other highly qualified personnel, which will benefit Canada by providing access to individuals skilled in the discovery and analysis of natural products.