Resistance is futile: hijacking bacterial signal transduction pathways to increase antibiotic uptake

磷霉素通过细菌表面的特定通道进入细菌，该通道被细菌的信号通路激活。这种信号是由一种叫做葡萄糖-6-磷酸的碳水化合物分子自然触发的。改变这个小分子的结构可以增强这个触发器的作用，即使我们只使用少量的药物，也会导致药物在细菌中的量增加。这种策略具有巨大的潜力，可以通过大量涌入药物分子来压倒细菌，从而使细菌内药物的积累超过药物修饰的速度，从而打破细菌的耐药性。我们观察到，用氟修饰葡萄糖-6-磷酸可以极大地增强信号通路，即使比临床剂量少得多，也可以增加磷霉素的效果。基于这一观察结果，在本项目中，我们将系统地修改和测试葡萄糖-6-磷酸，以了解哪些结构元件对信号传导有最大的增强作用。我们将开发一种材料，可以在哺乳动物细胞内传递基于g6p的分子，这样我们的策略也可以用于休眠状态的病原体。我们的愿景是通过提供细菌目标的激活剂而不是抑制剂，从根本上改变对抗抗菌素耐药性的方式。该项目的成功还将揭示增强旧抗生素作为对抗抗菌素耐药性手段的巨大潜力。

Fosfomycin enters bacteria through a defined channel on the bacterial surface, which is activated by a signalling pathway in bacteria. This signalling is naturally triggered by a small carbohydrate molecule called glucose-6-phosphate. Modification of the structure of this small molecule can result in an enhanced effect of this trigger, which will lead to the increased amount of the drug in bacteria even if we use only a small amount of drug. This strategy has a huge potential to break the resistance of bacteria by overwhelming bacteria with influx of drug molecules so that the accumulation of drug inside bacteria exceeds the speed of drug modification. We have observed that modifying glucose-6-phosphate with fluorine could enormously enhance the signalling pathway, and could increase the effect of fosfomycin even at a much less amount than the clinical dose. Based on this observation, in this proposed project, we will systematically modify and test glucose-6-phosphate to see what structural element will have the most enhancing effect on signalling. The, we will develop a material that can deliver the G6P-based molecule inside mammalian cells so that our strategy can also work on pathogens in the dormant state. Our vision is to fundamentally change the way to fight the antimicrobial resistance by providing an activator of the bacterial target, not an inhibitor. The success of this project will also shed the light on the great potential of potentiating old antibiotics as a means to fight against antimicrobial resistance.