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

磷霉素通过细菌表面的一条明确的通道进入细菌，该通道由细菌中的信号通路激活。这种信号自然是由一种名为葡萄糖-6-磷酸的小碳水化合物分子触发的。这种小分子的结构修饰可以导致这种触发作用的增强，这将导致细菌中药物含量的增加，即使我们只使用少量的药物。这一策略具有巨大的潜力，通过用大量药物分子压倒细菌来打破细菌的耐药性，从而使药物在细菌内的积累超过药物修饰的速度。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，即使在远低于临床剂量的情况下，也可以增加磷霉素的效果。基于这一观察，在这个拟议的项目中，我们将系统地修饰和测试葡萄糖-6-磷酸，以确定哪些结构元素将对信号转导具有最大的增强作用。此外，我们将开发一种材料，可以在哺乳动物细胞内运送基于G6P的分子，这样我们的策略也可以对处于休眠状态的病原体起作用。我们的愿景是通过提供细菌靶标的激活剂而不是抑制物来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加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.