Abiological enzymatic C-H functionalization for bioactive molecule construction and diversification

用于生物活性分子构建和多样化的非生物酶 C-H 功能化

• 批准号: 10397244
• 负责人: FRANCES H ARNOLD
• 金额: $ 6.89万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397244
• 关键词: Amination; Amines; Anti-Bacterial Agents; Antibiotics; Bacteria; Bacterial Infections; Binding; Bypass; Chemicals; Chemosensitization; Complex; Cytochrome P450; Development; Directed Molecular Evolution; Drug usage; Effectiveness; Engineering; Enzymes; Escherichia coli; Evolution; Gram-Negative Bacteria; Growth; Heme; Hydrogen Bonding; Infection; Left; Libraries; Membrane; Methods; Modification; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mutagenesis; Natural Products; Oxygen; Pharmaceutical Preparations; Process; Reaction; Research; Resistance; Serine; Site; Structure; Terpenes; VDAC1 gene; Variant; Walking; antimicrobial; bacterial resistance; base; drug development; effectiveness study; functional group; immune clearance; improved; in silico; innovation; insight; nitrene; novel; preservation; pressure; screening; success

PROJECT SUMMARY/ABSTRACT Antibiotics are antibacterial drugs used to treat bacterial infections by killing the bacteria or inhibiting bacterial growth to allow immune clearance. While antibiotics help treat infections, their use puts selective pressure on bacteria and inevitably leads to the emergence of resistant bacteria. Additionally, the development of novel antibiotics has slowed in recent years which has left us with fewer treatment options for multidrug-resistant bacterial infections. Moreover, most of these problematic multidrug-resistant bacteria are gram-negative, meaning they are double-membraned and thus intrinsically resistant to many drugs, making drug development even more challenging. There is a dire need for innovative approaches to develop new antibiotics that are effective against gram-negative bacteria so we can preserve our ability to treat these infections. Promising studies have shown that the addition of primary amines can improve drug accumulation into gram-negative bacteria for various compounds, making it a rational and feasible approach to increase the activity of promising antibacterials by improving their bacterial permeation. Synthetically aminating bioactive compounds can be onerous, typically requiring multiple steps and the addition of other functional groups before acquiring the desired amine. In contrast, directed evolution of cytochromes P450 is a promising strategy to develop enzymatic platforms for the late-stage modifications of bioactive compounds. The ability of P450 enzymes to functionalize the inert yet ubiquitous C–H bonds in bioactive compounds can be exploited to facilitate the diversification of natural products. Recent successes have expanded the natural activity of P450s to include primary amination of benzylic and allylic C(sp3) – H bonds via C–H nitrene insertion. Here, I propose to expand further this primary amination activity to include substrates that are natural antibacterials. Our approach to engineering enzymes to directly aminate C–H bonds will provide a means to accelerate the amination of antibacterials. Streamlining the amination process of antibacterials will in turn facilitate downstream studies so the antibacterial potential of these aminated derivatives can be thoroughly investigated. These methods will help establish engineered aminases for antibacterials as a proof of concept that can be expanded to help potentiate various antibacterials.

项目总结/文摘