Mechanisms in RiPP Natural Product Biosynthesis

天然产物是由生物体产生的化合物，具有多种生物、生态和人类学功能，最显著的是作为治疗各种人类疾病的药物。事实上，美国食品和药物管理局批准用于人类的大多数药物要么是天然产物，要么是天然产物的合成衍生物，这清楚地强调了这些分子对21世纪人类生活质量的重要性。然而，近年来，由于抗菌素耐药性的广泛出现，许多传统上用于治疗人类细菌感染的天然产品已经失去了效力。鉴于这一令人生畏的威胁，迫切需要重新努力发现和开发新的抗微生物天然产品。拟议的研究计划旨在通过几个不同但有凝聚力的研究方向来解决这一日益严重的危机，旨在阐明构建天然产物的酶的机制原理。最初的研究将集中在发展几种新兴的生物物理方法，从独特的角度来表征生物合成酶。这些研究将提供一种分子机制的理解，使生物合成酶能够发挥其功能，并将为如何潜在地为合成目的而操纵这些功能提供见解。此外，该计划将识别和表征具有异常结构的分子和具有异常功能的酶，分别作为鉴定新的抗菌化合物和化合物结构修饰的新工具的潜在途径。总之,理解

Natural products are chemical compounds made by living organisms that serve numerous biological, ecological, and anthropological functions most notably as medicines to treat a variety of human illnesses. Indeed, the majority of all drugs approved for human use by the US Food and Drug Administration are either natural products or are synthetic derivatives of natural products, clearly underscoring the importance of these molecules to the quality of human life in the 21st century. In recent years, however, many of the natural products that have been traditionally used to treat human bacterial infections have lost their effectiveness due to the widespread emergence of antimicrobial resistance. In light of this daunting threat, renewed efforts in discovering and developing novel antimicrobial natural products are urgently needed. The proposed research program seeks to address this growing crisis through several distinct, but cohesive research directions that aim to illuminate the mechanistic principles of the enzymes that construct natural products. Initial studies will be focused on developing several emerging biophysical methods to characterize biosynthetic enzymes from unique perspectives. These studies will provide a molecular mechanistic understanding of what enables biosynthetic enzymes to perform their functions, and will provide insights into how those functions may potentially be manipulated for synthetic purposes. In addition, the program will identify and characterize molecules with unusual structures and enzymes with unusual functions, as potential avenues for identifying new antimicrobial compounds and new tools for the structural modification of compounds, respectively. Altogether, understanding natural product biosynthesis on a molecular mechanistic level provides a critical foundation for guiding the characterization of new natural products, for the rational engineering of structures that do not exist in nature, a-nd for the targeted production of molecules of interest. As such, the proposed research program is expected to greatly benefit the ongoing and mounting struggle to combat drug resistant human pathogens - an endeavor of immense importance to the people of Canada and across the world.