全球由碳青霉烯类耐药革兰氏阴性病原体引起的临床感染发病率不断增加，需要紧急而有效的治疗策略。抗生素佐剂是增强美罗培南对抗碳青霉烯类耐药细菌功效的有前途的方法。这项研究表明，通过基于细胞的高通量筛选，抗癌剂5-氟尿嘧啶（5-FU，50 µM）可将美罗培南对blaNDM-5阳性大肠杆菌的最低抑制浓度显着降低32倍。进一步的药理学研究表明，5-FU 对碳青霉烯类抗生素对 42 种产生金属-β-内酰胺酶 (MBL)（如 NDM 和 IMP）或丝氨酸 β-内酰胺酶（Ser-BL）（如 KPC）的革兰氏阴性菌表现出增强作用和 OXA。这些细菌包括大肠杆菌、肺炎克雷伯菌、铜绿假单胞菌和不动杆菌，其中 32 种是从人类临床样本中获得的。机制研究表明，5-FU 抑制 blaNDM-5 基因的转录和表达。此外，5-FU与美罗培南联用可增强细菌代谢，刺激活性氧（ROS）的产生，从而使细菌对美罗培南更敏感。在小鼠全身感染模型中，5-FU联合美罗培南降低了细菌负荷，有效提高了83.3%的存活率，而美罗培南单药治疗的存活率为16.7%。总的来说，这些发现表明 5-FU 作为一种新型美罗培南佐剂，有可能改善碳青霉烯类耐药细菌引起的感染的治疗结果。版权所有 © 2024 Elsevier Ltd 和国际抗菌化疗协会。版权所有。

The global increasing incidence of clinical infections caused by carbapenem-resistant Gram-negative pathogens requires urgent and effective treatment strategies. Antibiotic adjuvants represent a promising approach to enhance the efficacy of meropenem against carbapenem-resistant bacteria. This study shows that the anticancer agent 5-fluorouracil (5-FU, 50 µM) significantly reduced the minimum 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 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., 32 of which were obtained from human clinical samples. Mechanistic investigations revealed that 5-FU inhibited the transcription and expression of the blaNDM-5 gene. In addition, 5-FU combined with meropenem enhanced bacterial metabolism, and stimulated the production of reactive oxygen species (ROS), thereby rendering bacteria more susceptible to meropenem. In a mouse systemic infection model, 5-FU combined with meropenem reduced bacterial loads and effectively elevated the survival rate of 83.3%, compared with 16.7% with meropenem monotherapy. Collectively, these findings indicate the potential of 5-FU as a novel meropenem adjuvant to improve treatment outcomes against infections caused by carbapenem-resistant bacteria.Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.