Leveraging the Iron-Probe-MurB Interaction: An Enhanced Platform for PET Imaging of Bacterial Infections

Abstract

Abstract 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.