Discovery of High-level Antibiotic Resistance Mechanisms in Nature.

自然界中高级抗生素耐药机制的发现。

• 批准号: BB/X000613/1
• 负责人: Maximiliano Gutierrez
• 金额: $ 53.3万
• 依托单位: The Francis Crick Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX000613%2F1
• 关键词: Discovery; level; Antibiotic; Resistance; Mechanisms

Pathogenic bacteria are rapidly evolving resistance to antibiotic treatment. This fact is one of the greatest challenges in modern medicine and agriculture. If this trend is not reversed in the next decades, is estimated that 10 million people a year will die from antibiotic resistant infections by 2050.The methods that bacteria can use to avoid being killed by antibiotics are very diverse and many of them are still unknown. If we could have a comprehensive and detailed catalogue of the existing mechanisms of antibiotic resistance, we could (a) be better informed to choose the best antibiotic to treat an infection by a particular bacteria (b) find or design new drugs to counteract these resistance mechanisms, so that the "resistance neutralising" drug can then be prescribed together with the antibiotic. An example of this combination therapy is the antibiotic amoxicillin that is commonly given to patients with another drug called clavulanic acid. This is because resistant bacteria make a protein that breaks down the amoxicillin, but clavulanic acid inactivates this protein. The clavulanic acid-bound inactive bacterial protein, leaves the amoxicillin intact and therefore able to kill the bacteria.In this project, we aim to discover and to understand a variety of mechanisms of antibiotic resistance in a group of bacteria known as the mycobacteria. This group includes a number of important human and animal pathogens, causing hard to treat diseases such as human and bovine tuberculosis, leprosy and Buruli ulcer, among others.Upon completion we will have (i) tested the sensitivity/resistance of 48 different species of mycobacteria against 40 antibiotics currently in use in the clinic (ii) identified and characterised the mechanism(s) used by the bacteria to become resistant to these antibiotics. These mechanisms normally involve the production of proteins that can somehow render the antibiotic inactive, and we will find the proteins responsible and the mode of antibiotic inactivation.We will focus our study on mycobacteria, but different groups of bacteria tend to share mechanisms of resistance. We therefore expect that our discoveries will also impact on the understanding and treatment of many other bacterial infections of humans and animals.

病原菌对抗生素治疗迅速产生耐药性。这是现代医学和农业面临的最大挑战之一。如果这一趋势在未来几十年内得不到扭转，估计到2050年，每年将有1000万人死于抗生素耐药性感染。细菌可以用来避免被抗生素杀死的方法非常多样，其中许多方法仍然是未知的。如果我们能有一个全面和详细的目录，现有的抗生素耐药性的机制，我们可以（a）更好地了解选择最好的抗生素，以治疗感染的特定细菌（B）发现或设计新的药物，以抵消这些耐药性机制，使“耐药性中和”药物可以与抗生素一起处方。这种联合治疗的一个例子是抗生素阿莫西林，通常与另一种药物克拉维酸一起给予患者。这是因为耐药细菌产生一种分解阿莫西林的蛋白质，但克拉维酸使这种蛋白质失活。克拉维酸结合的无活性细菌蛋白质使阿莫西林保持完整，因此能够杀死细菌。在这个项目中，我们的目标是发现和了解一组称为分枝杆菌的细菌中的抗生素耐药性的各种机制。这一组包括一些重要的人类和动物病原体，导致难以治疗的疾病，如人类和牛结核病、麻风病和布鲁里溃疡，完成后，我们将（i）测试48种不同分枝杆菌对目前临床使用的40种抗生素的敏感性/耐药性（ii）确定和描述机制细菌利用它来对这些抗生素产生耐药性。这些机制通常涉及蛋白质的产生，这些蛋白质可以以某种方式使抗生素失活，我们将找到负责的蛋白质和抗生素失活的模式。我们将集中研究分枝杆菌，但不同的细菌群体往往有共同的耐药机制。因此，我们希望我们的发现也将对人类和动物的许多其他细菌感染的理解和治疗产生影响。