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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=713960
• 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 -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.

抗生素耐药细菌的出现和扩散引起了许多对我们治疗感染能力的关注。这重现了对发现新抗生素的发现以及制定治疗此类感染的策略的研究。对抗细菌病原体的一些最佳解决方案来自自然的天然产物的形式，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，这些基因主要存在是某些微生物。 -lactam的天然产品家族包括诸如青霉素和头孢菌素抗生素等成员，它们的使用历史悠久。它们也是最广泛使用的抗生素类，但是-lactam抗性始终带来了挑战。某些酶可以化学灭活青霉素和头孢菌素抗生素会引起耐药性。克拉维酸是一种天然产生的这种酶的抑制剂，当与青霉素型抗生素结合使用时，它恢复了抗生素对原本抗性病原体作用的能力。克拉夫酸酸是使用链霉菌链霉菌的工业生产的。导致克拉夫酸产生的生物合成途径仅部分知道，有关该过程中涉及的所有基因的详细信息也缺乏。众所周知，链霉菌会产生许多具有药物重要的化合物，并且对它们进行研究非常兴趣，目的是寻找提高天然产物产量并鉴定新分子的方法。在过去的二十年中，发现链霉菌包含可能生产许多天然产物的预测基因，但在实验室条件下只生产了少数基因。因此，这些所谓的“未知或神秘”天然产品可能是人类和兽医使用的未来药物的来源。我工作的长期目标是充分了解控制克拉维烷酸和其他天然产物在链球菌和相关细菌中的生物合成的机制。该研究计划将在知识的产生中做出重大贡献，该知识可用于生成新的应用分子。此外，它将培训学生和其他高素质的人员，这将通过提供熟练的自然产品发现和分析的个人来使加拿大受益。