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Positron Emission Tomography Imaging of Acinetobacter baumannii Infection: Comparison of Gallium-68 Labeled Siderophores

. 2025 Apr 11 ; 11 (4) : 917-928. [epub] 20250318

Language English Country United States Media print-electronic

Document type Journal Article, Comparative Study

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.

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Giamarellou H.; Antoniadou A.; Kanellakopoulou K. Acinetobacter baumannii: A Universal Threat to Public Health?. Int. J. Antimicrob. Agents 2008, 32 (2), 106–119. 10.1016/j.ijantimicag.2008.02.013. PubMed DOI

Ramirez M. S.; Bonomo R. A.; Tolmasky M. E. Carbapenemases: Transforming Acinetobacter baumannii into Yet a More Dangerous Menace. Biomolecules 2020, 10 (5), 720.10.3390/biom10050720. PubMed DOI PMC

Lee C. R.; Lee J. H.; Park M.; Park K. S.; Bae I. K.; Kim Y. B.; Cha C. J.; Jeong B. C.; Lee S. H. Biology of Acinetobacter baumannii: Pathogenesis, Antibiotic Resistance Mechanisms, and Prospective Treatment Options. Front. Cell. Infect. Microbiol. 2017, 7, 55.10.3389/fcimb.2017.00055. PubMed DOI PMC

Peleg A. Y.; Seifert H.; Paterson D. L. Acinetobacter baumannii: Emergence of a Successful Pathogen. Clin. Microbiol. Rev. 2008, 21 (3), 538–582. 10.1128/CMR.00058-07. PubMed DOI PMC

Tacconelli E.; Carrara E.; Savoldi A.; Harbarth S.; Mendelson M.; Monnet D. L.; Pulcini C.; Kahlmeter G.; Kluytmans J.; Carmeli Y.; Ouellette M.; Outterson K.; Patel J.; Cavaleri M.; Cox E. M.; Houchens C. R.; Grayson M. L.; Hansen P.; Singh N.; Theuretzbacher U.; Magrini N.; Aboderin A. O.; Al-Abri S. S.; Awang Jalil N.; Benzonana N.; Bhattacharya S.; Brink A. J.; Burkert F. R.; Cars O.; Cornaglia G.; Dyar O. J.; Friedrich A. W.; Gales A. C.; Gandra S.; Giske C. G.; Goff D. A.; Goossens H.; Gottlieb T.; Guzman Blanco M.; Hryniewicz W.; Kattula D.; Jinks T.; Kanj S. S.; Kerr L.; Kieny M. P.; Kim Y. S.; Kozlov R. S.; Labarca J.; Laxminarayan R.; Leder K.; Leibovici L.; Levy-Hara G.; Littman J.; Malhotra-Kumar S.; Manchanda V.; Moja L.; Ndoye B.; Pan A.; Paterson D. L.; Paul M.; Qiu H.; Ramon-Pardo P.; Rodríguez-Baño J.; Sanguinetti M.; Sengupta S.; Sharland M.; Si-Mehand M.; Silver L. L.; Song W.; Steinbakk M.; Thomsen J.; Thwaites G. E.; van der Meer J. W.; Van Kinh N.; Vega S.; Villegas M. V.; Wechsler-Fördös A.; Wertheim H. F. L.; Wesangula E.; Woodford N.; Yilmaz F. O.; Zorzet A. Discovery, Research, and Development of New Antibiotics: The WHO Priority List of Antibiotic-Resistant Bacteria and Tuberculosis. Lancet Infect. Dis. 2018, 18 (3), 318–327. 10.1016/S1473-3099(17)30753-3. PubMed DOI

Bostanghadiri N.; Narimisa N.; Mirshekar M.; Dadgar-Zankbar L.; Taki E.; Navidifar T.; Darban-Sarokhalil D. Prevalence of Colistin Resistance in Clinical Isolates of Acinetobacter baumannii: A Systematic Review and Meta-Analysis. Antimicrob. Resist. Infect. Control 2024, 13 (1), 24.10.1186/s13756-024-01376-7. PubMed DOI PMC

Ayobami O.; Willrich N.; Harder T.; Okeke I. N.; Eckmanns T.; Markwart R. The Incidence and Prevalence of Hospital-Acquired (Carbapenem-Resistant) Acinetobacter baumannii in Europe, Eastern Mediterranean and Africa: A Systematic Review and Meta-Analysis. Emerging Microbes Infect. 2019, 8 (1), 1747–1759. 10.1080/22221751.2019.1698273. PubMed DOI PMC

Katsaragakis S.; Markogiannakis H.; Toutouzas K. G.; Drimousis P.; Larentzakis A.; Theodoraki E. M.; Theodorou D. Acinetobacter baumannii Infections in a Surgical Intensive Care Unit: Predictors of Multi-Drug Resistance. World J. Surg. 2008, 32 (6), 1194–1202. 10.1007/s00268-008-9571-3. PubMed DOI

Bergogne-Bérézin E.; Towner K. J. Acinetobacter spp. as Nosocomial Pathogens: Microbiological, Clinical, and Epidemiological Features. Clin. Microbiol. Rev. 1996, 9 (2), 148–165. 10.1128/CMR.9.2.148. PubMed DOI PMC

Falagas M. E.; Rafailidis P. I. Attributable Mortality of Acinetobacter baumannii: No Longer a Controversial Issue. Crit. Care 2007, 11 (3), 134.10.1186/cc5911. PubMed DOI PMC

Nguyen M.; Joshi S. G. Carbapenem Resistance in Acinetobacter baumannii, and Their Importance in Hospital-Acquired Infections: A Scientific Review. J. Appl. Microbiol. 2021, 131 (6), 2715–2738. 10.1111/jam.15130. PubMed DOI

Metersky M. L.; Kalil A. C. New Guidelines for Nosocomial Pneumonia. Curr. Opin. Pulm. Med. 2017, 23 (3), 211–217. 10.1097/MCP.0000000000000367. PubMed DOI

Lee C. Y.; Degani I.; Cheong J.; Weissleder R.; Lee J. H.; Cheon J.; Lee H. Development of Integrated Systems for On-Site Infection Detection. Acc. Chem. Res. 2021, 54 (21), 3991–4000. 10.1021/acs.accounts.1c00498. PubMed DOI PMC

Bartal C.; Rolston K. V. I.; Nesher L. Carbapenem-Resistant Acinetobacter baumannii: Colonization, Infection and Current Treatment Options. Infect. Dis. Ther. 2022, 11 (2), 683–694. 10.1007/s40121-022-00597-w. PubMed DOI PMC

Berton D. C.; Kalil A. C.; Teixeira P. J. Z. Quantitative versus Qualitative Cultures of Respiratory Secretions for Clinical Outcomes in Patients with Ventilator-Associated Pneumonia. Cochrane Database Syst. Rev. 2014, 2014 (10), CD006482.10.1002/14651858.CD006482.pub4. PubMed DOI PMC

Khasheii B.; Mahmoodi P.; Mohammadzadeh A. Siderophores: Importance in Bacterial Pathogenesis and Applications in Medicine and Industry. Microbiol. Res. 2021, 250, 126790.10.1016/j.micres.2021.126790. PubMed DOI

Khan A.; Singh P.; Srivastava A. Synthesis, Nature and Utility of Universal Iron Chelator – Siderophore: A Review. Microbiol. Res. 2018, 212–213, 103–111. 10.1016/j.micres.2017.10.012. PubMed DOI

Ferreira D.; Seca A. M. L.; Pinto D. C. G. A.; Silva A. M. S. Targeting Human Pathogenic Bacteria by Siderophores: A Proteomics Review. J. Proteonomics 2016, 145, 153–166. 10.1016/j.jprot.2016.04.006. PubMed DOI

Fardeau S.; Mullié C.; Dassonville-Klimpt A.; Audic N.; Sasaki A.; Sonnet P.. Bacterial Iron Uptake: A Promising Solution Against Multidrug Resistant Bacteria. In Science against Microbial Pathogens: Communicating Current Research and Technological Advances; Formatex Research Center, 2011; Vol. 1, pp 695–705.

Yakkala H.; Samantarrai D.; Gribskov M.; Siddavattam D. Comparative Genome Analysis Reveals Nichespecific Genome Expansion in Acinetobacter baumannii Strains. PLoS One 2019, 14 (6), e021820410.1371/journal.pone.0218204. PubMed DOI PMC

Funahashi T.; Tanabe T.; Mihara K.; Miyamoto K.; Tsujibo H.; Yamamoto S. Identification and Characterization of an Outer Membrane Receptor Gene in Acinetobacter Baumannii Required for Utilization of Desferricoprogen, Rhodotorulic Acid, and Desferrioxamine B as Xenosiderophores. Biol. Pharm. Bull. 2012, 35 (5), 753–760. 10.1248/bpb.35.753. PubMed DOI

Petrik M.; Haas H.; Schrettl M.; Helbok A.; Blatzer M.; Decristoforo C. In Vitro and In Vivo Evaluation of Selected 68Ga-Siderophores for Infection Imaging. Nucl. Med. Biol. 2012, 39 (3), 361–369. 10.1016/j.nucmedbio.2011.09.012. PubMed DOI PMC

Petrik M.; Umlaufova E.; Raclavsky V.; Palyzova A.; Havlicek V.; Haas H.; Novy Z.; Dolezal D.; Hajduch M.; Decristoforo C. Imaging of Pseudomonas aeruginosa Infection with Ga-68 Labelled Pyoverdine for Positron Emission Tomography. Sci. Rep. 2018, 8 (1), 15698.10.1038/s41598-018-33895-w. PubMed DOI PMC

Petrik M.; Haas H.; Dobrozemsky G.; Lass-Flörl C.; Helbok A.; Blatzer M.; Dietrich H.; Decristoforo C. 68Ga-Siderophores for PET Imaging of Invasive Pulmonary Aspergillosis: Proof of Principle. J. Nucl. Med. 2010, 51 (4), 639–645. 10.2967/jnumed.109.072462. PubMed DOI PMC

Petrik M.; Umlaufova E.; Raclavsky V.; Palyzova A.; Havlicek V.; Pfister J.; Mair C.; Novy Z.; Popper M.; Hajduch M.; Decristoforo C. 68Ga-labelled Desferrioxamine-B for Bacterial Infection Imaging. Eur. J. Nucl. Med. Mol. Imaging 2021, 48 (2), 372–382. 10.1007/s00259-020-04948-y. PubMed DOI PMC

Petrik M.; Franssen G. M.; Haas H.; Laverman P.; Hörtnagl C.; Schrettl M.; Helbok A.; Lass-Flörl C.; Decristoforo C. Preclinical Evaluation of Two 68Ga-siderophores as Potential Radiopharmaceuticals for Aspergillus fumigatus Infection Imaging. Eur. J. Nucl. Med. Mol. Imaging 2012, 39 (7), 1175–1183. 10.1007/s00259-012-2110-3. PubMed DOI PMC

Krasulova K.; Neuzilova B.; Dvorakova Bendova K.; Novy Z.; Popper M.; Hajduch M.; Petrik M. Preclinical Characterisation of Gallium-68 Labeled Ferrichrome Siderophore Stereoisomers for PET Imaging Applications. EJNMMI Radiopharm. Chem. 2024, 9 (1), 20.10.1186/s41181-024-00249-z. PubMed DOI PMC

Murdoch D. R.; O’Brien K. L.; Driscoll A. J.; Karron R. A.; Bhat N. Laboratory Methods for Determining Pneumonia Etiology In Children. Clin. Infect. Dis. 2012, 54 (suppl_2), S146–S152. 10.1093/cid/cir1073. PubMed DOI

Boers S. A.; Jansen R.; Hays J. P. Understanding and Overcoming the Pitfalls and Biases of Next-Generation Sequencing (NGS) Methods for Use in the Routine Clinical Microbiological Diagnostic Laboratory. Eur. J. Clin. Microbiol. Infect. Dis. 2019, 38 (6), 1059–1070. 10.1007/s10096-019-03520-3. PubMed DOI PMC

Polvoy I.; Flavell R. R.; Rosenberg O. S.; Ohliger M. A.; Wilson D. M. Nuclear Imaging of Bacterial Infection: The State of the Art and Future Directions. J. Nucl. Med. 2020, 61 (12), 1708–1716. 10.2967/jnumed.120.244939. PubMed DOI PMC

Vaidyanathan S.; Patel C. N.; Scarsbrook A. F.; Chowdhury F. U. FDG PET/CT in Infection and Inflammation - Current and Emerging Clinical Applications. Clin. Radiol. 2015, 70 (7), 787–800. 10.1016/j.crad.2015.03.010. PubMed DOI

Mota F.; Ordonez A. A.; Firth G.; Ruiz-Bedoya C. A.; Ma M. T.; Jain S. K. Radiotracer Development for Bacterial Imaging. J. Med. Chem. 2020, 63 (5), 1964–1977. 10.1021/acs.jmedchem.9b01623. PubMed DOI PMC

Ordonez A. A.; Jain S. K. Pathogen-Specific Bacterial Imaging in Nuclear Medicine. Semin. Nucl. Med. 2018, 48 (2), 182–194. 10.1053/j.semnuclmed.2017.11.003. PubMed DOI PMC

van Oosten M.; Hahn M.; Crane L. M. A.; Pleijhuis R. G.; Francis K. P.; van Dijl J. M.; van Dam G. M. Targeted Imaging of Bacterial Infections: Advances, Hurdles and Hopes. FEMS Microbiol. Rev. 2015, 39 (6), 892–916. 10.1093/femsre/fuv029. PubMed DOI

Bendova K.; Raclavsky V.; Novotny R.; Luptakova D.; Popper M.; Novy Z.; Hajduch M.; Petrik M. [68Ga]Ga-Ornibactin for Burkholderia cepacia complex Infection Imaging Using Positron Emission Tomography. J. Med. Chem. 2023, 66 (11), 7584–7593. 10.1021/acs.jmedchem.3c00469. PubMed DOI PMC

Cook-Libin S.; Sykes E. M. E.; Kornelsen V.; Kumar A. Iron Acquisition Mechanisms and Their Role in the Virulence of Acinetobacter baumannii. Infect. Immun. 2022, 90 (10), e0022310.1128/iai.00223-22. PubMed DOI PMC

Aghajani Z.; Rasooli I.; Mousavi Gargari S. L. Exploitation of two siderophore receptors, BauA and BfnH, for protection against Acinetobacter baumannii infection. APMIS 2019, 127 (12), 753–763. 10.1111/apm.12992. PubMed DOI

Tiwari V.; Rajeswari M. R.; Tiwari M. Proteomic Analysis of Iron-Regulated Membrane Proteins Identify FhuE Receptor as a Target to Inhibit Siderophore-Mediated Iron Acquisition in Acinetobacter baumannii. Int. J. Biol. Macromol. 2019, 125, 1156–1167. 10.1016/j.ijbiomac.2018.12.173. PubMed DOI

Maingot M.; Bourotte M.; Vetter A. C.; Schellhorn B.; Antraygues K.; Scherer H.; Gitzinger M.; Kemmer C.; Dale G. E.; Defert O.; Lociuro S.; Brönstrup M.; Willand N.; Trebosc V. Structure-Activity Relationships of Actively FhuE Transported Rifabutin Derivatives with Potent Activity Against Acinetobacter baumannii. Eur. J. Med. Chem. 2023, 252, 115257.10.1016/j.ejmech.2023.115257. PubMed DOI

Bohac T. J.; Fang L.; Giblin D. E.; Wencewicz T. A. Fimsbactin and Acinetobactin Compete for the Periplasmic Siderophore Binding Protein BauB in Pathogenic Acinetobacter baumannii. ACS Chem. Biol. 2019, 14 (4), 674–687. 10.1021/acschembio.8b01051. PubMed DOI

Sokol P. A.; Darling P.; Lewenza S.; Corbett C. R.; Kooi C. D. Identification of a Siderophore Receptor Required for Ferric Ornibactin Uptake in Burkholderia Cepacia. Infect. Immun. 2000, 68 (12), 6554–6560. 10.1128/IAI.68.12.6554-6560.2000. PubMed DOI PMC

Artuso I.; Poddar H.; Evans B. A.; Visca P. Genomics of Acinetobacter baumannii iron uptake. Microb. Genomes 2023, 9 (8), mgen001080.10.1099/mgen.0.001080. PubMed DOI PMC

Balbontín R.; Villagra N.; Pardos de la Gándara M.; Mora G.; Figueroa-Bossi N.; Bossi L. Expression of IroN, the Salmochelin Siderophore Receptor, Requires mRNA Activation by RyhB Small RNA Homologues. Mol. Microbiol. 2016, 100 (1), 139–155. 10.1111/mmi.13307. PubMed DOI

Emery T. A. Model for Carrier-Mediated Iron Transport. Biochim. Biophys. Acta 1974, 363, 219–225. 10.1016/0005-2736(74)90061-3. PubMed DOI

Murakami C.; Tanaka A. R.; Sato Y.; Kimura Y.; Morimoto K. Easy Detection of Siderophore Production in Diluted Growth Media Using an Improved CAS Reagent. J. Microbiol. Methods 2021, 189, 106310.10.1016/j.mimet.2021.106310. PubMed DOI

CLSI . Performance Standards for Antimicrobial Susceptibility Testing. In Clinical and Laboratory Standards Institute; 35th ed. 2025.

Aguiar M.; Orasch T.; Misslinger M.; Dietl A. M.; Gsaller F.; Haas H. The Siderophore Transporters sit1 and sit2 Are Essential for Utilization of Ferrichrome-, Ferrioxamine- and Coprogen-type Siderophores in Aspergillus fumigatus. J. Fungi 2021, 7 (9), 768.10.3390/jof7090768. PubMed DOI PMC

Protchenko O.; Ferea T.; Rashford J.; Tiedeman J.; Brown P. O.; Botstein D.; Philpott C. C. Three Cell Wall Mannoproteins Facilitate the Uptake of Iron in Saccharomyces cerevisiae. J. Biol. Chem. 2001, 276 (52), 49244–49250. 10.1074/jbc.M109220200. PubMed DOI

Sheldon J. R.; Skaar E. P. Acinetobacter baumannii Can Use Multiple Siderophores for Iron Acquisition, but Only Acinetobactin is Required for Virulence. PLoS Pathog. 2020, 16 (10), e100899510.1371/journal.ppat.1008995. PubMed DOI PMC

Luna C. M.; Vujacich P.; Niederman M. S.; Vay C.; Gherardi C.; Matera J.; Jolly E. C. Impact of BAL Data on the Therapy and Outcome of Ventilator-Associated Pneumonia: 676 Clinical Investigations in Critical. Care 1997, 111 (3), 676–685. 10.1378/chest.111.3.676. PubMed DOI

Guerra L. F.; Baughman R. P. Use of Bronchoalveolar Lavage to Diagnose Bacterial Pneumonia in Mechanically Ventilated Patients. Crit. Care Med. 1990, 18 (2), 169–173. 10.1097/00003246-199002000-00009. PubMed DOI

Nomanpour B.; Ghodousi A.; Babaei A.; Abtahi H.; Tabrizi M.; Feizabadi M. Rapid, cost-effective, sensitive and quantitative detection of Acinetobacter baumannii from pneumonia patients. Iran. J. Microbiol. 2011, 3 (4), 162–169. PubMed PMC

Petrik M.; Knetsch P. A.; Knopp R.; Imperato G.; Ocak M.; Von Guggenberg E.; Haubner R.; Silbernagl R.; Decristoforo C. Radiolabelling of Peptides for PET, SPECT and Therapeutic Applications Using a Fully Automated Disposable Cassette System. Nucl. Med. Commun. 2011, 32 (10), 887–895. 10.1097/MNM.0b013e3283497188. PubMed DOI

Thompson M. G.; Black C. C.; Pavlicek R. L.; Honnold C. L.; Wise M. C.; Alamneh Y. A.; Moon J. K.; Kessler J. L.; Si Y.; Williams R.; Yildirim S.; Kirkup B. C.; Green R. K.; Hall E. R.; Palys T. J.; Zurawski D. V. Validation of a Novel Murine Wound Model of Acinetobacter baumannii Infection. Antimicrob. Agents Chemother. 2014, 58 (3), 1332–1342. 10.1128/AAC.01944-13. PubMed DOI PMC

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