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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Jun 22

PMID 38907990

Authors

Andrzej Mular

Isabella Hubmann

Milos Petrik

Katerina Bendova

Barbora Neuzilova

Mario Aguiar

Patricia Caballero

Abraham Shanzer

Henryk Kozlowski

Hubertus Haas

Clemens Decristoforo

Elzbieta Gumienna-Kontecka

Affiliations

Soon will be listed here.

Abstract

The pathogenic fungus 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. [Ga]Ga(III)-FOXE analogues were internalized in cells via Sit1. Uptake of [Ga]Ga(III)-FOX 2-5, the most structurally alike analogue to FOXE, was high by both and bacterial . 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 compared to that by , whereas lengthening the ring (FOX 2-6 and 3-5) had the opposite effect. These results were consistent both and , 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.

References

Misslinger M, Petrik M, Pfister J, Hubmann I, Bendova K, Decristoforo C . Desferrioxamine B-Mediated Pre-Clinical In Vivo Imaging of Infection by the Mold Fungus . J Fungi (Basel). 2021; 7(9). PMC: 8472378. DOI: 10.3390/jof7090734. View

Jurkevitch E, Hadar Y, Chen Y, Libman J, Shanzer A . Iron uptake and molecular recognition in Pseudomonas putida: receptor mapping with ferrichrome and its biomimetic analogs. J Bacteriol. 1992; 174(1):78-83. PMC: 205679. DOI: 10.1128/jb.174.1.78-83.1992. View

Berner I, Jung G, Winkelmann G . Characterization of ferrioxamine E as the principal siderophore of Erwinia herbicola (Enterobacter agglomerans). Biol Met. 1988; 1(1):51-6. DOI: 10.1007/BF01128017. View

Essen S, Johnsson A, Bylund D, Pedersen K, Lundstrom U . Siderophore production by Pseudomonas stutzeri under aerobic and anaerobic conditions. Appl Environ Microbiol. 2007; 73(18):5857-64. PMC: 2074896. DOI: 10.1128/AEM.00072-07. View

Park Y, Kim J, Yun C . Identification of ferrichrome- and ferrioxamine B-mediated iron uptake by Aspergillus fumigatus. Biochem J. 2016; 473(9):1203-13. DOI: 10.1042/BCJ20160066. View

Swayambhu G, Bruno M, Gulick A, Pfeifer B . Siderophore natural products as pharmaceutical agents. Curr Opin Biotechnol. 2021; 69:242-251. DOI: 10.1016/j.copbio.2021.01.021. View

Hissen A, Chow J, Pinto L, Moore M . Survival of Aspergillus fumigatus in serum involves removal of iron from transferrin: the role of siderophores. Infect Immun. 2004; 72(3):1402-8. PMC: 356059. DOI: 10.1128/IAI.72.3.1402-1408.2004. View

Mular A, Shanzer A, Kozlowski H, Hubmann I, Misslinger M, Krzywik J . Cyclic Analogs of Desferrioxamine E Siderophore for Ga Nuclear Imaging: Coordination Chemistry and Biological Activity in . Inorg Chem. 2021; 60(23):17846-17857. PMC: 8653149. DOI: 10.1021/acs.inorgchem.1c02453. View

Endicott N, Lee E, Wencewicz T . Structural Basis for Xenosiderophore Utilization by the Human Pathogen Staphylococcus aureus. ACS Infect Dis. 2017; 3(7):542-553. DOI: 10.1021/acsinfecdis.7b00036. View

10.

Aguiar M, Orasch T, Shadkchan Y, Caballero P, Pfister J, Sastre-Velasquez L . Uptake of the Siderophore Triacetylfusarinine C, but Not Fusarinine C, Is Crucial for Virulence of Aspergillus fumigatus. mBio. 2022; 13(5):e0219222. PMC: 9600649. DOI: 10.1128/mbio.02192-22. View

11.

Kwon-Chung K, Sugui J . Aspergillus fumigatus--what makes the species a ubiquitous human fungal pathogen?. PLoS Pathog. 2013; 9(12):e1003743. PMC: 3857757. DOI: 10.1371/journal.ppat.1003743. View

12.

Osiewacz H, Schurmanns L . A Network of Pathways Controlling Cellular Homeostasis Affects the Onset of Senescence in . J Fungi (Basel). 2021; 7(4). PMC: 8065454. DOI: 10.3390/jof7040263. View

13.

Normant V, Josts I, Kuhn L, Perraud Q, Fritsch S, Hammann P . Nocardamine-Dependent Iron Uptake in : Exclusive Involvement of the FoxA Outer Membrane Transporter. ACS Chem Biol. 2020; 15(10):2741-2751. DOI: 10.1021/acschembio.0c00535. View

14.

Sebulsky M, Shilton B, Speziali C, Heinrichs D . The role of FhuD2 in iron(III)-hydroxamate transport in Staphylococcus aureus. Demonstration that FhuD2 binds iron(III)-hydroxamates but with minimal conformational change and implication of mutations on transport. J Biol Chem. 2003; 278(50):49890-900. DOI: 10.1074/jbc.M305073200. View

15.

Wang W, Qiu Z, Tan H, Cao L . Siderophore production by actinobacteria. Biometals. 2014; 27(4):623-31. DOI: 10.1007/s10534-014-9739-2. View

16.

Sebulsky M, Speziali C, Shilton B, Edgell D, Heinrichs D . FhuD1, a ferric hydroxamate-binding lipoprotein in Staphylococcus aureus: a case of gene duplication and lateral transfer. J Biol Chem. 2004; 279(51):53152-9. DOI: 10.1074/jbc.M409793200. View

17.

Kornreich-Leshem H, Ziv C, Gumienna-Kontecka E, Arad-Yellin R, Chen Y, Elhabiri M . Ferrioxamine B analogues: targeting the FoxA uptake system in the pathogenic Yersinia enterocolitica. J Am Chem Soc. 2005; 127(4):1137-45. DOI: 10.1021/ja035182m. View

18.

Mariotti P, Malito E, Biancucci M, Lo Surdo P, Mishra R, Nardi-Dei V . Structural and functional characterization of the Staphylococcus aureus virulence factor and vaccine candidate FhuD2. Biochem J. 2012; 449(3):683-93. DOI: 10.1042/BJ20121426. View

19.

Petrik M, Franssen G, Haas H, Laverman P, Hortnagl C, Schrettl M . Preclinical evaluation of two 68Ga-siderophores as potential radiopharmaceuticals for Aspergillus fumigatus infection imaging. Eur J Nucl Med Mol Imaging. 2012; 39(7):1175-83. PMC: 3369139. DOI: 10.1007/s00259-012-2110-3. View

20.

Petrik M, Haas H, Laverman P, Schrettl M, Franssen G, Blatzer M . 68Ga-triacetylfusarinine C and 68Ga-ferrioxamine E for Aspergillus infection imaging: uptake specificity in various microorganisms. Mol Imaging Biol. 2013; 16(1):102-8. PMC: 3823598. DOI: 10.1007/s11307-013-0654-7. View