Translation of ceragenin affinity for bacteria to an imaging reagent for infection.

Nilantha Bandara,Yubo Li,Xiaobo Gu,Cedric Mpoy,Buck E. Rogers,Shenglou Deng,Philipp Diebolder,Paul B. Savage,Pitambar Khanal

doi:10.1039/c9ra02226k

Nilantha Bandara, Yubo Li + Show 7 more

Open Access

https://doi.org/10.1039/c9ra02226k

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Abstract

Responses to bacterial infections may be manifest systemically without evidence of the location of the infection site. A rapid means of pinpointing infection sites would be useful in providing effective and possibly localized treatment. Successful means of identifying infection sites would require two components: (1) a molecule capable of recognizing bacteria and (2) a means of communicating recognition. For the recognition element, we used a ceragenin, a small molecule with affinity for bacterial membranes that was designed as a mimic of endogenous antimicrobial peptides. For the communication element, we used 64Cu, which is a positron emitter. By conjugating a copper chelating group to the ceragenin, the two elements were combined. Chelation of 64Cu by the conjugate was effective and provided a stable complex that allowed in vivo imaging. When administered to mice in a thigh infection model, the 64Cu-labeled conjugate accumulated at the site of infection (right thigh) without accumulation at the complementary site (left thigh). This conjugate may provide a means of identifying infection sites in patients presenting general signs of infection without localized symptoms.

Highlights

Identi cation of sites of bacterial infection is important for proper clinical care of patients manifesting general signs of infection
Multiple small molecules are known to associate with bacteria; for example, polymyxins bind the lipid A portion of lipopolysaccharides found in the outer membranes of Gram-negative aDepartment of Radiation Oncology, Washington University School of Medicine, St
An oligo-ethylene glycol linker was used to separate the ceragenin and NOTA to ensure that the bound copper ion did not interfere with interactions with bacterial membranes

Summary

Introduction

Identi cation of sites of bacterial infection is important for proper clinical care of patients manifesting general signs of infection (e.g., fever and elevated white blood cell counts). A key element for imaging infections is a targeting motif in a molecule that provides for selective association with bacteria. By conjugating a ceragenin (bacteria targeting) to an appropriate metal chelating group (for complexing a positron-emitting radiometal), we generated compounds with features necessary for selectively imaging infections.

Results

Conclusion