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

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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.