Acinetobacter baumannii (AB) is an opportunistic pathogen with growing clinical relevance due to its increasing level of antimicrobial resistance in the last few decades. In the event of an AB hospital outbreak, fast detection and localization of the pathogen is crucial, to prevent its further spread. However, contemporary diagnostic tools do not always meet the requirements for rapid and accurate diagnosis. For this reason, we report here the possibility of using gallium-68 labeled siderophores, bacterial iron chelators, for positron emission tomography imaging of AB infections. In our study, we radiolabeled several siderophores and tested their in vitro uptake in AB cultures. Based on the results and the in vitro properties of studied siderophores, we selected two of them for further in vivo testing in infectious models. Both selected siderophores, ferrioxamine E and ferrirubin, showed promising in vitro characteristics. In vivo, we observed rapid pharmacokinetics and no excessive accumulation in organs other than the excretory organs in normal mice. We demonstrated that the radiolabeled siderophores accumulate in AB-infected tissue in three animal models: a murine model of myositis, a murine model of dorsal wound infection and a rat model of pneumonia. These results suggest that both siderophores radiolabeled with Ga-68 could be used for PET imaging of AB infection.

• Klíčová slova
• Acinetobacter baumannii, PET, gallium-68, radiolabeling, siderophores,
• MeSH
• Acinetobacter baumannii * MeSH
• infekce bakteriemi rodu Acinetobacter * diagnostické zobrazování   mikrobiologie   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• pozitronová emisní tomografie * metody   MeSH
• radioizotopy galia * chemie   MeSH
• siderofory * chemie   farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• Gallium-68 MeSH Prohlížeč
• radioizotopy galia * MeSH
• siderofory * MeSH

The pathogenic fungus Aspergillus fumigatus utilizes a cyclic ferrioxamine E (FOXE) siderophore to acquire iron from the host. Biomimetic FOXE analogues were labeled with gallium-68 for molecular imaging with PET. [68Ga]Ga(III)-FOXE analogues were internalized in A. fumigatus cells via Sit1. Uptake of [68Ga]Ga(III)-FOX 2-5, the most structurally alike analogue to FOXE, was high by both A. fumigatus and bacterial Staphylococcus aureus. However, altering the ring size provoked species-specific uptake between these two microbes: ring size shortening by one methylene unit (FOX 2-4) increased uptake by A. fumigatus compared to that by S. aureus, whereas lengthening the ring (FOX 2-6 and 3-5) had the opposite effect. These results were consistent both in vitro and in vivo, including PET imaging in infection models. Overall, this study provided valuable structural insights into the specificity of siderophore uptake and, for the first time, opened up ways for selective targeting and imaging of microbial pathogens by siderophore derivatization.

• MeSH
• Aspergillus fumigatus * metabolismus   chemie   MeSH
• aspergilóza * diagnostické zobrazování   mikrobiologie   MeSH
• biomimetické materiály chemie   metabolismus   MeSH
• cyklické peptidy MeSH
• deferoxamin chemie   MeSH
• druhová specificita MeSH
• myši MeSH
• pozitronová emisní tomografie * metody   MeSH
• radioizotopy galia * chemie   MeSH
• siderofory * chemie   metabolismus   MeSH
• Staphylococcus aureus * metabolismus   MeSH
• železité sloučeniny chemie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cyklické peptidy MeSH
• deferoxamin MeSH
• ferrioxamine E MeSH Prohlížeč
• Gallium-68 MeSH Prohlížeč
• radioizotopy galia * MeSH
• siderofory * MeSH
• železité sloučeniny MeSH

BACKGROUND: Siderophores are small iron-binding molecules produced by microorganisms to facilitate iron acquisition from the environment. Radiolabelled siderophores offer a promising solution for infection imaging, as they can specifically target the pathophysiological mechanisms of pathogens. Gallium-68 can replace the iron in siderophores, enabling molecular imaging with positron emission tomography (PET). Stereospecific interactions play a crucial role in the recognition of receptors, transporters, and iron utilisation. Furthermore, these interactions have an impact on the host environment, affecting pharmacokinetics and biodistribution. This study examines the influence of siderophore stereoisomerism on imaging properties, with a focus on ferrirubin (FR) and ferrirhodin (FRH), two cis-trans isomeric siderophores of the ferrichrome type. RESULTS: Tested siderophores were labelled with gallium-68 with high radiochemical purity. The resulting complexes differed in their in vitro characteristics. [68Ga]Ga-FRH showed less hydrophilic properties and higher protein binding values than [68Ga]Ga-FR. The stability studies confirmed the high radiochemical stability of both [68Ga]Ga-siderophores in all examined media. Both siderophores were found to be taken up by S. aureus, K. pneumoniae and P. aeruginosa with similar efficacy. The biodistribution tested in normal mice showed rapid renal clearance with low blood pool retention and fast clearance from examined organs for [68Ga]Ga-FR, whereas [68Ga]Ga-FRH showed moderate retention in blood, resulting in slower pharmacokinetics. PET/CT imaging of mice injected with [68Ga]Ga-FR and [68Ga]Ga-FRH confirmed findings from ex vivo biodistribution studies. In a mouse model of S. aureus myositis, both radiolabeled siderophores showed radiotracer accumulation at the site of infection. CONCLUSIONS: The 68Ga-complexes of stereoisomers ferrirubin and ferrirhodin revealed different pharmacokinetic profiles. In vitro uptake was not affected by isomerism. Both compounds had uptake with the same bacterial culture with similar efficacy. PET/CT imaging showed that the [68Ga]Ga-complexes accumulate at the site of S. aureus infection, highlighting the potential of [68Ga]Ga-FR as a promising tool for infection imaging. In contrast, retention of the radioactivity in the blood was observed for [68Ga]Ga-FRH. In conclusion, the stereoisomerism of potential radiotracers should be considered, as even minor structural differences can influence their pharmacokinetics and, consequently, the results of PET imaging.

• Klíčová slova
• Imaging, Infection, Positron emission tomography, Siderophore, Stereoisomers,
• Publikační typ
• časopisecké články MeSH