A decade of ubiquicidin development for PET imaging of infection: A systematic review

Marjanovic-Painter, Biljana; Kleynhans, Janke; Zeevaart, Jan Rijn; Rohwer, Egmont Richard; Ebenhan, Thomas

doi:10.1016/j.nucmedbio.2022.11.001

Cited by 12 publications

(31 citation statements)

References 49 publications

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“…Multiple studies have demonstrated that 99m Tc labeled UBI (29–41) can successfully differentiate between bacterial infection and sterile inflammation (de Murphy et al 2010 ; Welling et al 2000 ). Further, a recent systematic review examining the progress of ubiquicidin-based PET imaging agents provided strong case for the use of [ 68 Ga]Ga-UBI as a PET based infection imaging agent (Marjanovic-Painter et al 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Expanding a peptide-covalent probe hybrid for PET imaging of S. aureus driven focal infections

Bhatt Mitra,

Chatterjee,

Kumar

et al. 2024

EJNMMI radiopharm. chem.

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Background The urgent demand for innovative theranostic strategies to combat bacterial resistance to antibiotics is evident, with substantial implications for global health. Rapid diagnosis of life-threatening infections can expedite treatment, improving patient outcomes. Leveraging diagnostic modalities i.e., positron emission tomography (PET) and single photon emission computed tomography (SPECT) for detecting focal infections has yielded promising results. Augmenting the sensitivity of current PET and SPECT tracers could enable effective imaging of pathogenic bacteria, including drug-resistant strains.UBI (29–41), an antimicrobial peptide (AMP) fragment recognizes the S. aureus membrane through electrostatic binding. Radiolabeled UBI (29–41) is a promising SPECT and PET-based tracer for detecting focal infections. 2-APBA (2-acetyl-phenyl-boronic acid), a non-natural amino acid, specifically targets lysyl-phosphatidyl-glycerol (lysyl-PG) on the S. aureus membranes, particularly in AMP-resistant strains. We propose that combining UBI with 2-APBA could enhance the diagnostic potential of radiolabeled UBI. Results Present work aimed to compare the diagnostic potential of two radiolabeled peptides, namely UBI (29–41) and 2-APBA modified UBI (29–41), referred to as UBI and UBI-APBA. APBA modification imparted antibacterial activity to the initially non-bactericidal UBI against S. aureus by inducing a loss of membrane potential. The antibacterial activity demonstrated by UBI-APBA can be ascribed to the synergistic interaction of both UBI and UBI-APBA on the bacterial membrane. To enable PET imaging, we attached the chelator 1,4,7-triazacyclononane 1-glutaric acid 4,7-acetic acid (NODAGA) to the peptides for complexation with the positron emitter Gallium-68 (68Ga). Both NODAGA conjugates were radiolabeled with 68Ga with high radiochemical purity. The resultant 68Ga complexes were stable in phosphate-buffered saline and human serum. Uptake of these complexes was observed in S. aureus but not in mice splenocytes, indicating the selective nature of their interaction. Additionally, the APBA conjugate exhibited superior uptake in S. aureus while preserving the selectivity of the parent peptide. Furthermore, [68Ga]Ga-UBI-APBA demonstrated accumulation at the site of infection in rats, with an improved target-to-non-target ratio, as evidenced by ex-vivo biodistribution and PET imaging. Conclusions Our findings suggest that linking UBI, as well as AMPs in general, with APBA shows promise as a strategy to augment the theranostic potential of these molecules.

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Section: Introductionmentioning

confidence: 99%

Expanding a peptide-covalent probe hybrid for PET imaging of S. aureus driven focal infections

Bhatt Mitra,

Chatterjee,

Kumar

et al. 2024

EJNMMI radiopharm. chem.

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Section: Introductionmentioning

confidence: 99%

“…Among AMPs, radiotracers based on ubiquicidin or UBI peptide are the most studied ones, which showed promising results in preclinical and clinical studies (Ferro‐Flores et al, 2016; Marjanovic‐Painter et al, 2023; Mukherjee et al, 2018). A recent review on a decade of development of UBI‐based tracers summarizes the studies done so far for developing positron emission tomography (PET) tracers (Marjanovic‐paineter et al, 2023). Although UBI (29–41) fragment radiolabeled with 99m Tc and 68 Ga is widely reported, an octapeptide derivative, UBI (31–38), had also shown promise as an infection imaging tracer (Ferreira et al, 2018; Strand et al, 2013; Welling et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Imaging of bacterial infection: Harnessing positron emission tomography and Cherenkov luminescence imaging with UBI‐derived octapeptide

Mitra

Mukherjee

Kumar

et al. 2023

Drug Development Research

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Noninvasive imaging techniques for the early detection of infections are in high demand. In this study, we present the development of an infection imaging agent consisting of the antimicrobial peptide fragment UBI (31–38) conjugated to the chelator 1,4,7‐triazacyclononane,1‐glutaric acid‐4,7‐acetic acid (NODAGA), which allows for labeling with the positron emitter Ga‐68. The preclinical evaluation of [68Ga]Ga–NODAGA–UBI (31–38) was conducted to investigate its potential for imaging bacterial infections caused by Staphylococcus aureus. The octapeptide derived from ubiquicidin, UBI (31–38), was synthesized and conjugated with the chelator NODAGA. The conjugate was then radiolabeled with Ga‐68. The radiolabeling process and the stability of the radio formulation were confirmed through chromatography. The study included both in vitro evaluations using S. aureus and in vivo evaluations in an animal model of infection and inflammation. Positron emission tomography (PET) and Cherenkov luminescence imaging (CLI) were performed to visualize the targeted localization of the radio formulation at the site of infection. Ex vivo biodistribution studies were carried out to quantify the uptake of the radio formulation in different organs and tissues. Additionally, the uptake of [18F]Fluorodeoxyglucose ([18F] FDG) in the animal model was also studied for comparison. The [68Ga]Ga–NODAGA–UBI (31–38) complex consistently exhibited high radiochemical purity (>90%) after formulation. The complex demonstrated stability in saline, phosphate‐buffered saline, and human serum for up to 3 h. Notably, the complex displayed significantly higher uptake in S. aureus, which was inhibited in the presence of unconjugated UBI (29–41) peptide, confirming the specificity of the formulation for bacterial membranes. Bacterial imaging capability was also observed in PET and CLI images. Biodistribution results indicated a substantial target‐to‐nontarget ratio of approximately 4 at 1 h postinjection of the radio formulation. Conversely, the uptake of [18F]FDG in the animal model did not allow for the discrimination of infected and inflamed sites. Our studies have demonstrated that [68Ga]Ga–NODAGA–UBI (31–38) holds promise as a radiotracer for imaging bacterial infections caused by S. aureus.

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“…This specific binding is not dependent on leukocyte function. [1][2][3] For this reason, 68 Ga-DOTA-UBI (29-41) or 68 Ga-UBI can be used as a PET/CT radiotracer to differentiate infection from inflammation 4,5 by identifying viable bacteria. Table 1 presents the criteria adopted to assess its concentration, 6 and Table 2 presents the findings of this pilot study.…”

mentioning

confidence: 99%

“…Ubiquicidin is a fragment of a cationic peptide that preferentially binds to a negatively charged bacterial cell membrane, and its absorption reflects the bacterial charge. This specific binding is not dependent on leukocyte function 1–3 . For this reason, 68 Ga-DOTA-UBI (29–41) or 68 Ga-UBI can be used as a PET/CT radiotracer to differentiate infection from inflammation 4,5 by identifying viable bacteria.…”

mentioning

confidence: 99%

Could 68Ga-DOTA-UBI-29-41 Help Identify Chronic Osteomyelitis on PET/CT Images? A Pilot Study

Nogueira,

de Barboza,

Dell’Aquila

et al. 2023

Clin Nucl Med

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This pilot study aimed to confirm the presence of infectious agents in infection foci using PET/CT imaging with 68Ga-DOTA-UBI (29–41) in 7 patients with chronic osteomyelitis and with indications for surgical cleaning at the site of the infection focus. The whole-body PET/CT was performed on Biograph mCT 40 PET/CT scanner (Siemens Healthineers); the image began 45–60 minutes postinjection of the radiotracer (148–260 MBq). This study demonstrated that, in 6 patients in whom the PET/CT was classified as positive for identified infectious foci, confirmed by culture of the secretion sample collected during surgery, only 1 patient in antibiotic therapy was negative.

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A decade of ubiquicidin development for PET imaging of infection: A systematic review

Cited by 12 publications

References 49 publications

Expanding a peptide-covalent probe hybrid for PET imaging of S. aureus driven focal infections

Expanding a peptide-covalent probe hybrid for PET imaging of S. aureus driven focal infections

Imaging of bacterial infection: Harnessing positron emission tomography and Cherenkov luminescence imaging with UBI‐derived octapeptide

Could 68Ga-DOTA-UBI-29-41 Help Identify Chronic Osteomyelitis on PET/CT Images? A Pilot Study

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