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

棒状链霉菌和其他相关链霉菌物种中生物活性次级代谢产物的调节和生物合成

• 批准号: RGPIN-2018-05949
• 负责人: Tahlan, Kapil
• 金额: $ 3.06万
• 依托单位: Memorial University of Newfoundland
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=666399
• 关键词: Regulation; biosynthesis; bioactive; secondary; metabolites

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.

抗生素耐药细菌的出现和传播引发了人们对我们治疗由它们引起的感染的能力的许多担忧。这重振了对发现新抗生素和设计治疗此类感染的策略的研究。一些对抗细菌病原体的最佳解决方案来自自然产品，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使用特定的途径和基因集合成的，这些基因大多存在于某些微生物群体中。β-内酰胺类天然产品包括青霉素和头孢菌素类抗生素，这些抗生素在人类的使用历史很长。它们也是使用最广泛的抗生素类别，但对β-内酰胺类抗生素的耐药性一直是一个挑战。某些酶可以通过化学方法使青霉素和头孢菌素类抗生素失活，从而产生耐药性。克拉维酸是一种天然产生的此类酶的抑制剂，当与青霉素类抗生素联合使用时，它可以恢复抗生素对抗耐药病原体的能力。克拉维酸是用棒状链霉菌生产的。导致克拉维酸产生的生物合成途径只有一部分人知道，关于参与这一过程的所有基因的细节也是缺乏的。众所周知，链霉菌能产生许多药用上重要的化合物，人们对研究这些化合物非常感兴趣，目的是找到提高天然产物产量和鉴定新分子的方法。在过去的二十年里，人们发现链霉菌含有可能制造许多天然产品的预测基因，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”的天然产品可能成为未来人类和兽医用药的来源。我工作的长期目标是充分了解棒状链霉菌和相关细菌中克拉维酸和其他天然产物的生物合成机制。这项研究计划将在产生可用于生产新应用的分子的知识方面做出重大贡献。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，因为它提供了接触到拥有发现和分析天然产品技能的个人的途径。