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The growing prevalence of antimicrobial resistance underscores the need for alternative or complementary strategies to enhance antibiotic activity. Fosfomycin (FOS) remains a recommended first-line treatment for uncomplicated UTIs due to its broad activity and low resistance rates; however, spontaneous resistance frequently arises through mutations in bacterial transport systems. Cranberry juice is known for its anti-adhesive and anti-infective properties; however, its potential to modulate antibiotic activity remains poorly understood. Here, we show that cranberry juice markedly potentiates the antibacterial activity of FOS and limits the emergence of resistance in UPEC clinical isolates. In 72% of the 32 tested isolates, cranberry juice significantly increased FOS inhibition activities and reduced spontaneous FOS-resistant mutant frequencies by up to five orders of magnitude. Whole-genome sequencing revealed distinct mutational patterns: FOS-resistant mutants selected without cranberry juice primarily carried\n                      <jats:italic toggle=\"yes\">glpT<\/jats:italic>\n                      mutations, whereas those obtained with juice harbored mutations in\n                      <jats:italic toggle=\"yes\">uhpT<\/jats:italic>\n                      or associated regulatory genes. Reporter assays indicated that cranberry juice represses\n                      <jats:italic toggle=\"yes\">glpT<\/jats:italic>\n                      expression while maintaining UhpT-mediated FOS uptake, thereby sustaining antibiotic entry and activity. These results demonstrate that cranberry juice alters bacterial carbohydrate transport regulation to potentiate FOS activity and suppress resistance emergence. This study provides novel evidence that a natural product can enhance FOS activity, highlighting its potential as an antibiotic adjuvant for UTI management.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Antimicrobial resistance is a growing threat to public health, and new strategies are needed to preserve the activity of existing antibiotics. This study reveals that cranberry juice, a widely consumed natural product, enhances the antibacterial activity of fosfomycin against uropathogenic\n                        <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                        by modulating bacterial sugar transport systems. By shifting fosfomycin uptake from GlpT- to UhpT-mediated pathways, cranberry juice both potentiates antibiotic activity and suppresses the emergence of resistant mutants. These findings provide new insight into how dietary components can influence antibiotic response, offering a promising basis for developing natural adjuvants that extend the lifespan of current antimicrobial agents.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/aem.02521-25","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T13:15:02Z","timestamp":1777900502000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Cranberry juice potentiates sensitivity of uropathogenic\n                    <i>Escherichia coli<\/i>\n                    (UPEC) strains to fosfomycin and decreases occurrence of spontaneous 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