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

抗生素耐药性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设计治疗此类感染的策略的研究注入了新的活力。一些对抗细菌病原体的最佳解决方案来自自然界，以天然产品的形式存在，其中还包括其他细菌产生的化合物。这些化合物中的大多数是使用专门的途径和基因组合成的，这些途径和基因组主要存在于某些微生物群中。天然产物的β-内酰胺家族包括诸如青霉素和头孢菌素抗生素的成员，其具有长期的人类使用历史。它们也是使用最广泛的一类抗生素，但β-内酰胺耐药性一直是一个挑战。某些酶可以化学地分解青霉素和头孢菌素类抗生素，引起耐药性。克拉维酸是这种酶的天然产生的抑制剂，当与青霉素类抗生素联合使用时，它恢复了抗生素对抗其他耐药病原体的能力。克拉维酸是使用细菌棒状链霉菌（Streptomyces clavuligerus）工业生产的。导致克拉维酸产生的生物合成途径仅部分已知，并且还缺乏关于该过程中所涉及的所有基因的细节。已知链霉菌产生许多医学上重要的化合物，并且人们对研究它们有很大的兴趣，目的是找到提高天然产物产量和鉴定新分子的方法。在过去的二十年中，人们发现链霉菌含有预测的基因，可能会产生许多天然产物，但只有少数是在实验室条件下产生的。因此，这些所谓的“未知或神秘”的天然产物可能是未来人类和兽医使用药物的来源。本研究的长期目标是全面了解克拉维酸和其他天然产物在S. clavuligerus和相关细菌。这项研究计划将大大有助于知识的产生，可用于生产新的应用分子。此外，它还将培训学生和其他高素质的人员，这将使加拿大受益，因为它提供了发现和分析自然产品的熟练人员。

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 β-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 β-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.