A new twist on drug design: AdhE spirosomes as cross species anti-virulence targets

抗生素已经使用多年，是治疗许多常见细菌感染的核心。然而，由于抗生素杀死细菌，它们的使用增加了对抗生素耐药的细菌的比例。这些耐药细菌是自然产生的突变体，与亲本类型的细菌略有不同：它们没有被杀死，也不再对普通抗生素敏感。这意味着迫切需要新的替代治疗形式。如果没有有效的抗生素，大手术和癌症化疗的成功将受到影响。此外，对于国民保健制度而言，耐药感染患者的保健费用高于非耐药感染患者的保健费用，原因是患病时间更长、需要进行额外的检查、使用更昂贵的药物以及住院的必要性增加。在所有引起问题的细菌中，革兰氏阴性家族是最难治疗的，因为它们会迅速产生耐药性。一种可能的替代治疗方法是通过关闭致病细菌的攻击性武器来降低它们的危险性。“关闭”细菌武器的化合物被称为“抗毒”化合物，因为它们不试图杀死细菌，只是降低它们的危险性。想象一下，拿走一支军队的所有关键武器，效果会小得多。我的实验室一直在开发和测试新的抗毒化合物。这些抗毒化合物对几种重要的革兰氏阴性细菌起作用，使它们成为一个令人兴奋的前景，但为了改善它们，我们必须确切地知道它们是如何起作用的。在我们之前的工作中，我们发现了一种叫做AdhE的蛋白质，它是这些抗毒化合物的靶标。如果从细菌中删除AdhE，它们引起疾病的能力就会降低。这告诉我们，AdhE是一个很好的靶点，可以据此建立和开发新的治疗方法。然而，如果没有蛋白质结构，就很难将先导化合物转化为有效治疗人类真正感染的药物。去年，我们与韩国的一个团队合作，解决了AdhE的结构问题，取得了重大突破。这是我们第一次处于激动人心的位置，我们有了一个真正的目标，它的高分辨率结构和我们想要改进的先导化合物。我们提出，通过这些结合到蛋白质上的先导化合物来解决AdhE的结构问题，将允许设计一个全新的抗感染药物家族，有助于预防或治疗各种革兰氏阴性病原体。在这项资助中，我们将跨越生物学和化学的几个方面来推进AdhE。我们在世界各地拥有相关领域专业知识的强大合作伙伴的支持下，希望帮助我们的项目。

Antibiotics have been used for many years and are central to the treatment of many common bacterial infections. However, because antibiotics kill bacteria, their use increases the proportion of bacteria that are resistant to antibiotics. These resistant bacteria are naturally occurring mutants that are slightly different from the parental type of bacteria: they are not killed and are no longer susceptible to common antibiotics. This means that there is an urgent need for new alternative forms of treatment. Without effective antibiotics, the success of major surgery and cancer chemotherapy will become compromised. Also, for the NHS, the cost of health care for patients with resistant infections is higher than care for patients with non-resistant infections due to longer duration of illness, additional tests, the use of more expensive drugs and the increased need for hospitalisation.Of all the bacteria that cause problems, the Gram-negative family are the hardest to treat because they rapidly develop resistance. One possible alternative treatment is to render the disease-causing bacteria less dangerous by turning off their offensive weapons. Compounds that "turn off' bacterial weapons are called "anti-virulence" compounds because they don't try to kill the bug, they just render them less dangerous. Imagine taking an army and removing all its key weapons- it's a lot less effective.My lab has been developing and testing new anti-virulence compounds. These anti-virulence compounds work against several important Gram-negative bacteria, making them an exciting prospect but, to improve them, we have to know exactly how they work. In our previous work, we found a protein, called AdhE, that is a target of these anti-virulence compounds. If AdhE is deleted from bacteria, they are less able to cause disease. This tells us that AdhE is a good target against which to base and develop new treatments. However, without a protein structure, it is very hard to convert the lead compounds into drugs that are effective in treating real infections in humans. A major breakthrough came last year when we worked with a group from Korea to solve the structure of AdhE. For the first time we are in the exciting position where we have a genuine target, its high resolution structure and lead compounds that we want to improve. We propose that solving the structure of AdhE with these lead compounds bound to the protein will allow the design of an entirely new family of anti-infective agents that could help to prevent or treat a wide range of Gram-negative pathogens. In this grant we will work across several aspects of biology and chemistry to move forward with AdhE. We are backed by strong collaborators around the world with expertise in related areas who want to help with our project.