Studies on Enzyme Mechanism and Antibiotic Resistance Strategies

酶机制及抗生素耐药策略研究

• 批准号: RGPIN-2019-05585
• 负责人: Tanner, Martin
• 金额: $ 2.62万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748120
• 关键词: Studies; Enzyme; Mechanism; Antibiotic; Resistance

The emergence of resistant strains of bacteria presents an ever-increasing problem to human health. The ability of bacteria to rapidly mutate and develop defense mechanisms against clinically used antibiotics means that we will soon run out of effective drugs to combat bacterial infections. This proposal describes three projects that will help us to understand and possibly control the bacterial defense mechanisms that allow them to survive in a human host. The first project involves an enzyme that produces a compound called staphyloxanthin that helps the pathogenic bacteria Staphylococcus aureus survive in the human body. Our proposal describes studies that will uncover how the enzyme constructs this molecule. Such knowledge can be used to prepare molecules that will prevent the enzyme from doing its job, and thereby depriving the bacteria of their defense mechanism. Such molecules could then be used as antibiotics. The second and third projects revolve around resistance mechanisms that bacteria use to evade clinically used antibiotics. In the second project we are targeting a protein called AmpG that plays a key role in resistance to the beta-lactam antibiotics, such as penicillin. When AmpG is functional it helps to "sense" the presence of the antibiotic and leads the bacteria to produce an enzyme called a beta-lactamase that then destroys the antibiotic. This renders the antibiotic ineffective and allows the infection to spread. We plan to study the way AmpG operates and discover which molecules are most effective at getting it to signal beta-lactamase production. Interfering with AmpG function could allow the beta-lactam antibiotics to function effectively once again. In the third project, we study an enzyme called ArnD that is involved in the resistance of certain pathogenic strains of bacteria against antibiotic peptides such as polymyxin. This enzyme helps to coat the surface of the bacteria with molecules that prevent the antibiotic from binding and killing the bacteria. We plan to demonstrate the activity of ArnD for the first time and to study how it generates the "coating" compounds. This may ultimately lead to the production of inhibitors of ArnD that could prevent it from functioning, thereby unmasking the bacteria and leaving them susceptible to antibiotics.

耐药菌株的出现给人类健康带来了日益严重的问题。细菌快速突变并形成针对临床使用抗生素的防御机制的能力意味着我们很快就会耗尽对抗细菌感染的有效药物。该提案描述了三个项目，将帮助我们了解并可能控制细菌防御机制，使它们能够在人类宿主中生存。 第一个项目涉及一种酶，它能产生一种叫做葡萄球菌黄质的化合物，帮助致病菌金黄色葡萄球菌在人体内生存。我们的提案描述了将揭示酶如何构建该分子的研究。这些知识可用于制备阻止酶发挥作用的分子，从而剥夺细菌的防御机制。这样的分子可以用作抗生素。 第二个和第三个项目围绕细菌用来逃避临床使用抗生素的耐药机制。在第二个项目中，我们的目标是一种名为 AmpG 的蛋白质，它在对青霉素等 β-内酰胺抗生素的耐药性中发挥着关键作用。当 AmpG 发挥作用时，它有助于“感知”抗生素的存在，并引导细菌产生一种称为 β-内酰胺酶的酶，然后破坏抗生素。这使得抗生素失效并导致感染扩散。我们计划研究 AmpG 的运作方式，并发现哪些分子最有效地使其发出 β-内酰胺酶产生的信号。干扰 AmpG 功能可以使 β-内酰胺抗生素再次有效发挥作用。 在第三个项目中，我们研究了一种名为 ArnD 的酶，它参与某些致病细菌菌株对多粘菌素等抗生素肽的抵抗力。这种酶有助于在细菌表面涂上分子，防止抗生素结合并杀死细菌。我们计划首次展示 ArnD 的活性并研究它如何生成“涂层”化合物。这可能最终导致 ArnD 抑制剂的产生，从而阻止其发挥作用，从而暴露细菌并使其对抗生素敏感。