Abstract Current adjuvant strategies to combat antimicrobial resistance such as β-lactamase inhibitors and efflux pump blockers prevent antibiotic degradation or export. We introduce a fundamentally different approach: exploiting bacterial nutrient sensing to drive antibiotic influx and overwhelm resistance. Fosfomycin is transported into bacterial cytoplasm via the glucose-6-phosphate (G6P) channel UhpT, which is activated by G6P. We demonstrate that fluorinated glucose-6-phosphate analogues showed superior activation of UhpT, leading to higher fosfomycin influx. In Escherichia coli , 3-fluoro-D-glucopyranosyl-6-phosphate showed 128-fold potentiation of fosfomycin, reversed fosA -mediated fosfomycin resistance, and displayed profound suppression of resistance evolution. In Staphylococcus aureus , 4-fluoro-D-glucopyranosyl-6-phosphate achieved 32-fold potentiation and broke fosB -mediated resistance. Furthermore, co-administration of these analogues improved Galleria mellonella survival (75-80%) versus fosfomycin monotherapy (30–40%). We demonstrate this high potentiation effect is combination of metabolic stability, persistent extracellular presence and favorable binding to the sensor protein. This influx-targeting strategy establishes a new paradigm to revive legacy antibiotics against multidrug-resistant pathogens.
Teahan et al. (Sun,) studied this question.