Anti-cancer agent 5-fluorouracil reverses meropenem resistance in carbapenem-resistant Gram-negative pathogens

Abstract

The global increasing incidence of clinical infections caused by carbapenem-resistant Gram-negative pathogens demands urgent and effective treatment strategies. Antibiotic adjuvants represent a promising approach to enhance the efficacy of meropenem against carbapenem-resistant bacteria. Herein, we identified the anticancer agent 5-fluorouracil (5-FU, 50 µM) significantly reduced the minimal inhibitory concentration of meropenem against blaNDM-5 positive Escherichia coli by 32-fold through cell-based high-throughput screening. Further pharmacological studies indicated that 5-FU exhibited the potentiation effects on carbapenem antibiotics against 42 Gram-negative bacteria producing either metallo-β-lactamases (MBLs), such as NDM and IMP, or serine β-lactamases (Ser-BLs), like KPC and OXA. These bacteria included E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter spp., with 32 of them obtained from human clinical samples. Mechanistic investigations revealed that 5-FU inhibited the transcriptional and expressional level of the blaNDM-5 gene. Additionally, the 5-FU combined with meropenem can enhance bacterial metabolism, and stimulate the production of Reactive Oxygen Species (ROS), thereby rendering bacteria more susceptible to meropenem. This drug combination could effectively elevate the survival rate from 16.7% to 83.3% compared to meropenem monotherapy, and reduce bacteria loads in tissues in a mouse systemic infection model. Collectively, these findings reveal that the potential of 5-FU as a novel meropenem adjuvant to improve treatment outcomes against carbapenem-resistant bacteria infections.