Imaging of Actively Proliferating Bacterial Infections by Targeting the Bacterial Metabolic Footprint with...

Since most d-amino acids (DAAs) are utilized by bacterial cells but not by mammalian eukaryotic hosts, recently DAA-based molecular imaging strategies have been extensively explored for noninvasively differentiating bacterial infections from the host's inflammatory responses. Given glutamine's pivotal role in bacterial survival, cell growth, biofilm formation, and even virulence, here we report a new positron emission tomography (PET) imaging approach using d-5-[¹¹C]glutamine (d-[5-¹¹C]-Gln) for potential clinical assessment of bacterial infection through a comparative study with its l-isomer counterpart, l-[5-¹¹C]-Gln. In both control and infected mice, l-[5-¹¹C]-Gln had substantially higher uptake levels than d-[5-¹¹C]-Gln in most organs except the kidneys, showing the expected higher use of l-[5-¹¹C]-Gln by mammalian tissues and more efficient renal excretion of d-[5-¹¹C]-Gln. Importantly, our work demonstrates that PET imaging with d-[5-¹¹C]-Gln is capable of detecting infections induced by both Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA) in a dual-infection murine myositis model with significantly higher infection-to-background contrast than with l-[5-¹¹C]-Gln (in E. coli, 1.64; in MRSA, 2.62, p = 0.0004). This can be attributed to the fact that d-[5-¹¹C]-Gln is utilized by bacteria while being more efficiently cleared from the host tissues. We confirmed the bacterial infection imaging specificity of d-[5-¹¹C]-Gln by comparing its uptake in active bacterial infections versus sterile inflammation and with 2-deoxy-2-[¹⁸F]fluoroglucose ([¹⁸F]FDG). These results together demonstrate the translational potential of PET imaging with d-[5-¹¹C]-Gln for the noninvasive detection of bacterial infectious diseases in humans.