Exogenous adenosine counteracts tigecycline resistance in tet (X3)-harboring Escherichia coli

作者：Jun Sun, Y. Liu, Jiashen Chang, Ying Liu, Luqi Li, Ran Jiang, Yihan Luo, Shuo Yang, Mei Yang, Xinglong Wang, Juan Wang, Xi Xia, Kangkang Guo, Zengqi Yang, Dongyang Ye · 发表于：Microbiology Spectrum · 年份：2025 · DOI：10.1128/spectrum.02382-24 · 被引用次数：1 · 研究领域：Antibiotic Resistance in Bacteria、Pharmaceutical and Antibiotic Environmental Impacts、Antibiotics Pharmacokinetics and Efficacy

ABSTRACT The rapid spread of antibiotic resistance poses a global health crisis. Tigecycline is a last-resort antibiotic, but the recent emergence of the plasmid-borne tet (X3) gene conferring high-level tigecycline resistance is deeply concerning. Here, we report a metabolomics-guided approach to overcome tet (X3)-mediated resistance. Using untargeted metabolomics, we identified adenosine as a key metabolic biomarker associated with tet (X3) expression. Remarkably, supplementation with exogenous adenosine was able to restore tigecycline susceptibility in tet (X3)-positive Escherichia coli both in vitro and in vivo . Our mechanistic investigations reveal that adenosine enhances the bactericidal effects of tigecycline by inducing oxidative stress, DNA/RNA damage, and cell membrane disruption in resistant bacteria. This study establishes a powerful metabolomics-driven strategy to potentiate antibiotic efficacy against drug-resistant pathogens. The adenosine-based adjuvant therapy represents a promising approach to combat the global crisis of antibiotic resistance. IMPORTANCE The emergence and widespread dissemination of the high-level tigecycline resistance gene tet (X3) have posed a significant challenge to the efficacy of tigecycline, which serves as the “last line of defense” against antimicrobial-resistant bacteria. Although tigecycline has not been approved for veterinary clinical use, constant detection of tet (X3) genes and new subtypes in livestock farming environments ...