Leveraging the Iron-Probe-MurB Interaction: An Enhanced Platform for PET Imaging of Bacterial Infections
Jianyang Fang, Lingxin Meng, Shouqiang Hong, Jingru Zhang, Xiaobo Wang, Hongwu Liu, Liwei Hong, Rongqiang Zhuang, Jinxiong Huang, Yesen Li, Xianzhong Zhang, Xilin Zhao, Zhide GuoAbstract
The accurate discrimination of bacterial infections from sterile inflammation is a critical yet unresolved challenge in clinical diagnostics. To address this, we designed and synthesized a series of 68Ga-labeled PET tracers derived from the FDA-approved iron chelator, deferasirox. The probes, denoted [68Ga]Ga-DFC2D, [68Ga]Ga-DFA2D, and [68Ga]Ga-DFA3D, were systematically evaluated for their Fe(III) chelation ability, stability, and bacteria-binding selectivity. In a murine model of bacterial myositis, [68Ga]Ga-DFA2D emerged as the lead candidate, demonstrating optimal pharmacokinetics and, most importantly, a remarkable ability to clearly differentiate bacterial infection from sterile inflammation. Preliminary mechanistic studies suggest that the exceptional targeting specificity of [68Ga]Ga-DFA2D may be attributed to its unique ability to form an iron-probe-MurB interaction mechanism, enhancing its uptake with bacterial targets. This work establishes a novel and robust strategy for developing bacteria-specific PET tracers, paving the way for the precise diagnosis and management of bacterial infections.