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<p>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 <i>Escherichia coli</i>, 3-fluoro-D-glucopyranosyl-6-phosphate showed 128-fold potentiation of fosfomycin, reversed <i>fosA</i>-mediated fosfomycin resistance, and displayed profound suppression of resistance evolution. In <i>Staphylococcus aureus</i>, 4-fluoro-D-glucopyranosyl-6-phosphate achieved 32-fold potentiation and broke <i>fosB</i>-mediated resistance. Furthermore, co-administration of these analogues improved <i>Galleria mellonella</i> 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.</p>

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Targeting bacterial influx pathways to defeat antibiotic resistance: fluorinated glucose-6-phosphate analogues revive fosfomycin efficacy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月21日

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  • Kirsty Alexandra Teahan,
  • Akhilesh Kumar Chaurasia,
  • Joohyun Lee,
  • Dong Hyeok Yoon,
  • Jacob Bilsborrow,
  • Tracey A. Newman,
  • Nicholas D. Evans,
  • Tae Hyung Won,
  • Seung Seo Lee,
  • Kyeong Kyu Kim

摘要

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.