Chen Fangfang, Li Yuyao, Peng Yan, Zhu Yifan, He Gao, Zhang Zhengwei, Xie Hexin
State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, P.R. China.
Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, 200235, China.
Adv Sci (Weinh). 2025 Feb;12(5):e2408559. doi: 10.1002/advs.202408559. Epub 2024 Dec 12.
The emergence of antibiotic resistance, particularly bacterial resistance to β-lactam antibiotics, the most widely prescribed therapeutic agents for infectious diseases, poses a significant threat to public health worldwide. The discovery of effective therapies against antibiotic-resistant pathogens has become an urgent need, necessitating innovative approaches to accelerate the identification and development of novel antibacterial agents. On the other hand, the expression of the β-lactam-hydrolyzing enzyme (β-lactamase), the major cause of bacterial resistance to β-lactam antibiotics, provides a distinctive opportunity to visualize bacterial infection, evaluate the efficacy of existing antibiotics, screen for novel antibacterial agents, and optimize drug dosing regimens in live animals. Herein, a hydrophilicity-switching, self-immobilizing, near-Infrared fluorogenic β-lactamase probe for the highly sensitive imaging of bacterial infection in live mice is reported. This probe, in addition to a significant increase in fluorescence upon selective hydrolysis by β-lactamases as conventional β-lactamase probes, also massively enriches within β-lactamase-expressing bacteria (over 1500-folds compared to the incubation medium), which renders excellent sensitivity in the imaging of bacterial infections in living animals. This agent has proven to enable the assessment of antibiotic therapeutic efficacy and potency of β-lactamase inhibitors in living animals in a non-invasive and much more convenient manner.
抗生素耐药性的出现，尤其是细菌对β-内酰胺抗生素（治疗传染病最广泛使用的治疗药物）的耐药性，对全球公共卫生构成了重大威胁。发现针对抗生素耐药病原体的有效疗法已成为当务之急，这需要创新方法来加速新型抗菌剂的鉴定和开发。另一方面，β-内酰胺水解酶（β-内酰胺酶）的表达是细菌对β-内酰胺抗生素耐药的主要原因，这为可视化细菌感染、评估现有抗生素的疗效、筛选新型抗菌剂以及在活体动物中优化给药方案提供了独特的机会。在此，报道了一种用于在活体小鼠中对细菌感染进行高灵敏度成像的亲水性切换、自固定、近红外荧光β-内酰胺酶探针。与传统的β-内酰胺酶探针一样，该探针在被β-内酰胺酶选择性水解后荧光显著增加，此外，它还能在表达β-内酰胺酶的细菌内大量富集（与孵育培养基相比超过1500倍），这使得在活体动物中对细菌感染成像具有出色的灵敏度。事实证明，这种试剂能够以非侵入性且更加便捷的方式评估活体动物中抗生素的治疗效果以及β-内酰胺酶抑制剂的效力。
