Bacteria from the Burkholderia cepacia complex are generally considered to be non-pathogenic to the healthy population. However, some of these species may cause serious nosocomial infections in immunocompromised patients; as such, it is essential to diagnose these infections rapidly so that adequate treatment can be initiated. We report here the use of a radiolabeled siderophore, ornibactin (ORNB), for positron emission tomography imaging. We successfully radiolabeled ORNB with gallium-68 with high radiochemical purity and proved that the resulting complex has optimal in vitro characteristics. In mice, the complex did not show excessive accumulation in organs and was excreted in the urine. We demonstrated that the [68Ga]Ga-ORNB complex accumulates at the site of Burkholderia multivorans infection, including pneumonia, in two animal infection models. These results suggest that [68Ga]Ga-ORNB is a promising tool for the diagnosis, monitoring, and evaluation of the therapeutic response to B. cepacia complex infection.

Department of Microbiology Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc 775 15 Czech Republic

Institute of Microbiology of the Czech Academy of Sciences Laboratory of Molecular Structure Characterization Prague 4 142 20 Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry and Czech Advanced Technology and Research Institute Palacky University Olomouc 779 00 Czech Republic

Laboratory of Experimental Medicine University Hospital Olomouc 779 00 Czech Republic

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Suetens C.; Latour K.; Kärki T.; Ricchizzi E.; Kinross P.; Moro M. L.; Jans B.; Hopkins S.; Hansen S.; Lyytikäinen O.; Reilly J.; Deptula A.; Zingg W.; Plachouras D.; Monnet D. L. Prevalence of Healthcare-Associated Infections, Estimated Incidence and Composite Antimicrobial Resistance Index in Acute Care Hospitals and Long-Term Care Facilities: Results from Two European Point Prevalence Surveys, 2016 to 2017. Eurosurveillance 2018, 23, 1–17. 10.2807/1560-7917.ES.2018.23.46.1800516. PubMed DOI PMC

Azoulay E.; Russell L.; Van de Louw A.; Metaxa V.; Bauer P.; Povoa P.; Montero J. G.; Loeches I. M.; Mehta S.; Puxty K.; Schellongowski P.; Rello J.; Mokart D.; Lemiale V.; Mirouse A. Diagnosis of Severe Respiratory Infections in Immunocompromised Patients. Intensive Care Med. 2020, 46, 298–314. 10.1007/s00134-019-05906-5. PubMed DOI PMC

Contejean A.; Lemiale V.; Resche-Rigon M.; Mokart D.; Pène F.; Kouatchet A.; Mayaux J.; Vincent F.; Nyunga M.; Bruneel F.; Rabbat A.; Perez P.; Meert A. P.; Benoit D.; Hamidfar R.; Darmon M.; Jourdain M.; Renault A.; Schlemmer B.; Azoulay E. Increased mortality in hematological malignancy patients with acute respiratory failure from undetermined etiology: a Groupe de Recherche en Réanimation Respiratoire en Onco-Hématologie (Grrr-OH) study. Ann. Intensive Care 2016, 6, 102–109. 10.1186/s13613-016-0202-0. PubMed DOI PMC

Cornelis P.; Dingemans J. Pseudomonas Aeruginosa Adapts Its Iron Uptake Strategies in Function of the Type of Infections. Front. Cell. Infect. Microbiol. 2013, 3, 1–7. 10.3389/fcimb.2013.00075. PubMed DOI PMC

Fan D.; Fang Q. Siderophores for Medical Applications: Imaging, Sensors, and Therapeutics. Int. J. Pharm. 2021, 597, 120306.10.1016/j.ijpharm.2021.120306. 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

Wilson B. R.; Bogdan A. R.; Miyazawa M.; Hashimoto K.; Tsuji Y. Siderophores in Iron Metabolism: From Mechanism to Therapy Potential. Trends Mol. Med. 2016, 22, 1077–1090. 10.1016/j.molmed.2016.10.005. PubMed DOI PMC

Ellermann M.; Arthur J. C. Siderophore-Mediated Iron Acquisition and Modulation of Host-Bacterial Interactions. Free Radic. Biol. Med. 2017, 105, 68–78. 10.1016/j.freeradbiomed.2016.10.489. PubMed DOI PMC

Butt A. T.; Thomas M. S. Iron Acquisition Mechanisms and Their Role in the Virulence of Burkholderia Species. Front. Cell. Infect. Microbiol. 2017, 7, 1–21. 10.3389/fcimb.2017.00460. PubMed DOI PMC

Jin Y.; Zhou J.; Zhou J.; Hu M.; Zhang Q.; Kong N.; Ren H.; Liang L.; Yue J. Genome-Based Classification of Burkholderia Cepacia Complex Provides New Insight into Its Taxonomic Status. Biol. Direct 2020, 15, 6–14. 10.1186/s13062-020-0258-5. PubMed DOI PMC

Compant S.; Nowak J.; Coenye T.; Clément C.; Ait Barka E. Diversity and Occurrence of Burkholderia Spp. in the Natural Environment. FEMS Microbiol. Rev. 2008, 32, 607–626. 10.1111/j.1574-6976.2008.00113.x. PubMed DOI

Häfliger E.; Atkinson A.; Marschall J. Systematic Review of Healthcare-Associated Burkholderia Cepacia Complex Outbreaks: Presentation, Causes and Outbreak Control. Infect. Prev. Pract. 2020, 2, 100082.10.1016/j.infpip.2020.100082. PubMed DOI PMC

Drevinek P.; Mahenthiralingam E. Burkholderia Cenocepacia in Cystic Fibrosis: Epidemiology and Molecular Mechanisms of Virulence. Clin. Microbiol. Infect. 2010, 16, 821–830. 10.1111/j.1469-0691.2010.03237.x. PubMed DOI

Sfeir M. M. Burkholderia Cepacia Complex Infections: More Complex than the Bacterium Name Suggest. J. Infect. 2018, 77, 166–170. 10.1016/j.jinf.2018.07.006. PubMed DOI

LiPuma J. J. The Changing Microbial Epidemiology in Cystic Fibrosis. Clin. Microbiol. Rev. 2010, 23, 299–323. 10.1128/CMR.00068-09. PubMed DOI PMC

Jones A. M.; Dodd M. E.; Govan J. R. W.; Barcus V.; Doherty C. J.; Morris J.; Webb A. K. Burkholderia Cenocepacia and Burkholderia Multivorans: Influence on Survival in Cystic Fibrosis. Thorax 2004, 59, 948–951. 10.1136/thx.2003.017210. PubMed DOI PMC

Hauser N.; Orsini J. Cepacia Syndrome in a Non-Cystic Fibrosis Patient. Case Rep. Infect. Dis. 2015, 2015, 1–4. 10.1155/2015/537627. PubMed DOI PMC

Rhodes K. A.; Schweizer H. P. Antibiotic Resistance in Burkholderia Species. Drug Resist. Updat. 2016, 28, 82–90. 10.1016/j.drup.2016.07.003. PubMed DOI PMC

Rose H.; Baldwin A.; Dowson C. G.; Mahenthiralingam E. Biocide Susceptibility of the Burkholderia Cepacia Complex. J. Antimicrob. Chemother. 2009, 63, 502–510. 10.1093/jac/dkn540. PubMed DOI PMC

Regan K. H.; Bhatt J. Eradication Therapy for Burkholderia Cepacia Complex in People with Cystic Fibrosis. Cochrane Database Syst. Rev. 2019, 4, CD009876.10.1002/14651858.CD009876.pub4. PubMed DOI PMC

Henry D.; Campbell M.; McGimpsey C.; Clarke A.; Louden L.; Burns J. L.; Roe M. H.; Vandamme P.; Speert D. Comparison of Isolation Media for Recovery of Burkholderia Cepacia Complex from Respiratory Secretions of Patients with Cystic Fibrosis. J. Clin. Microbiol. 1999, 37, 1004–1007. 10.1128/jcm.37.4.1004-1007.1999. PubMed DOI PMC

McMenamin J. D.; Zaccone T. M.; Coenye T.; Vandamme P.; LiPuma J. J. Misidentification of Burkholderia Cepacia in US Cystic Fibrosis Treatment Centers: An Analysis of 1,051 Recent Sputum Isolates. Chest 2000, 117, 1661–1665. 10.1378/chest.117.6.1661. PubMed DOI

Stephan H.; Freund S.; Beck W.; Jung G.; Meyer J. M.; Winkelmann G. Ornibactins-a New Family of Siderophores from Pseudomonas. BioMetals 1993, 6, 93–100. 10.1007/BF00140109. 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, 6554–6560. 10.1128/IAI.68.12.6554-6560.2000. PubMed DOI PMC

Visser M. B.; Majumdar S.; Hani E.; Sokol P. A. Importance of the Ornibactin and Pyochelin Siderophore Transport Systems in Burkholderia Cenocepacia Lung Infections. Infect. Immun. 2004, 72, 2850–2857. 10.1128/IAI.72.5.2850-2857.2004. PubMed DOI PMC

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, 361–369. 10.1016/j.nucmedbio.2011.09.012. 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, 639–645. 10.2967/jnumed.109.072462. 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, 15698–15699. 10.1038/s41598-018-33895-w. 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, 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, 1175–1183. 10.1007/s00259-012-2110-3. PubMed DOI PMC

Uematsu H.; Hashimoto H.; Iwamoto T.; Horiguchi H.; Yasunaga H. Impact of Guideline-Concordant Microbiological Testing on Outcomes of Pneumonia. Int. J. Qual. Heal. Care 2014, 26, 100–107. 10.1093/intqhc/mzt078. PubMed DOI

Auzin A.; Spits M.; Tacconelli E.; Rodríguez-Baño J.; Hulscher M.; Adang E.; Voss A.; Wertheim H. What Is the Evidence Base of Used Aggregated Antibiotic Resistance Percentages to Change Empirical Antibiotic Treatment? A Scoping Review. Clin. Microbiol. Infect. 2022, 28, 928–935. 10.1016/j.cmi.2021.12.003. PubMed DOI

Lanks C. W.; Musani A. I.; Hsia D. W. Community-Acquired Pneumonia and Hospital-Acquired Pneumonia. Med. Clin. North Am. 2019, 103, 487–501. 10.1016/j.mcna.2018.12.008. PubMed DOI

Heuker M.; Gomes A.; van Dijl J. M.; van Dam G. M.; Friedrich A. W.; Sinha B.; van Oosten M. Preclinical Studies and Prospective Clinical Applications for Bacteria-Targeted Imaging: The Future Is Bright. Clin. Transl. Imaging 2016, 4, 253–264. 10.1007/s40336-016-0190-y. 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, 1708–1716. 10.2967/jnumed.120.244939. PubMed DOI PMC

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

Signore A.; Bentivoglio V.; Varani M.; Lauri C. Current Status of SPECT Radiopharmaceuticals for Specific Bacteria Imaging. Semin. Nucl. Med. 2023, 53, 142–151. 10.1053/j.semnuclmed.2022.12.001. PubMed DOI

Ordonez A. A.; Sellmyer M. A.; Gowrishankar G.; Ruiz-Bedoya C. A.; Tucker E. W.; Palestro C. J.; Hammoud D. A.; Jain S. K. Molecular Imaging of Bacterial Infections: Overcoming the Barriers to Clinical Translation. Sci. Transl. Med. 2019, 11, eaax825110.1126/scitranslmed.aax8251. PubMed DOI PMC

Nairz M.; Weiss G. Iron in Infection and Immunity. Mol. Aspects Med. 2020, 75, 100864.10.1016/j.mam.2020.100864. PubMed DOI

Meyer J. M.; Van Van T.; Stintzi A.; Berge O.; Winkelmann G. Ornibactin Production and Transport Properties in Strains of Burkholderia Vietnamiensis and Burkholderia Cepacia (Formerly Pseudomonas Cepacia). BioMetals 1995, 8, 309–317. 10.1007/BF00141604. PubMed DOI

Eberl L.; Tümmler B. Pseudomonas Aeruginosa and Burkholderia Cepacia in Cystic Fibrosis: Genome Evolution, Interactions and Adaptation. Int. J. Med. Microbiol. 2004, 294, 123–131. 10.1016/j.ijmm.2004.06.022. PubMed DOI

Gautam V.; Singhal L.; Ray P. Burkholderia Cepacia Complex: Beyond Pseudomonas and Acinetobacter. Indian J. Med. Microbiol. 2011, 29, 4–12. 10.4103/0255-0857.76516. PubMed DOI

El-Laboudi A. H.; Etherington C.; Whitaker P.; Clifton I. J.; Conway S. P.; Denton M.; Peckham D. G. Acute Burkholderia Cenocepacia Pyomyositis in a Patient with Cystic Fibrosis. J. Cyst. Fibros. 2009, 8, 273–275. 10.1016/j.jcf.2009.04.007. PubMed DOI

Fadini G. P.; Tiengo A.; Avogaro A. First Isolation of Burkholderia Cepacia from a Deep Neck Abscess in a Diabetic Patient Successfully Treated with Hyperbaric Oxygen [3]Y. J. Clin. Microbiol. 2005, 43, 529.10.1128/JCM.43.1.529.2005. PubMed DOI PMC

Palmer K. L.; Mashburn L. M.; Singh P. K.; Whiteley M. Cystic Fibrosis Sputum Supports Growth and Cues Key Aspects of Pseudomonas Aeruginosa Physiology. J. Bacteriol. 2005, 187, 5267–5277. 10.1128/JB.187.15.5267-5277.2005. PubMed DOI 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, 887–895. 10.1097/MNM.0b013e3283497188. PubMed DOI

Biomimetic Analogues of the Desferrioxamine E Siderophore for PET Imaging of Invasive Aspergillosis: Targeting Properties and Species Specificity

Preclinical characterisation of gallium-68 labeled ferrichrome siderophore stereoisomers for PET imaging applications