title: Identification of the Ferric-Acinetobactin Outer Membrane Receptor in Aeromonas salmonicida subsp. salmonicida and Structure-Activity Relationships of Synthetic Acinetobactin Analogues.
abstract: Aeromonas salmonicida subsp. salmonicida, the causative agent of furunculosis in several fish species, produces acinetobactin and amonabactin as siderophores. In a previous study, we chemically characterized these siderophores and proposed a biosynthetic pathway based on genetic analysis. However, the internalization mechanisms of ferric-acinetobactin and ferric-amonabactin remain largely unknown. In the present study, we demonstrate that the outer membrane protein FstB is the ferric-acinetobactin receptor in A. salmonicida since an fstB defective mutant is unable to grow under iron limitation and does not use acinetobactin as an iron source. In order to study the effect that structural changes in acinetobactin have on its siderophore activity, a collection of acinetobactin-based analogues was synthesized, including its enantiomer and four demethylated derivatives. The biological activity of these analogues on an fstB(+) strain compared to an fstB(-) strain allowed structure-activity relationships to be elucidated. We found a lack of enantiomer preference on the siderophore activity of acinetobactin over A. salmonicida or on the molecular recognition by FstB protein receptor. In addition, it was observed that A. salmonicida could not use acinetobactin analogues when imidazole or a similar heterocyclic ring was absent from the structure. Surprisingly, removal of the methyl group at the isoxazolidinone ring induced a higher biological activity, thus suggesting alternative route(s) of entry into the cell that must be further investigated. It is proposed that some of the synthetic acinetobactin analogues described here could be used as starting points in the development of novel drugs against A. salmonicida and probably against other acinetobactin producers like the human pathogen Acinetobacter baumannii.
authors.affiliation: Department of Microbiology and Parasitology, Institute of Aquaculture, Universidade de Santiago de Compostela , Campus Sur, Santiago de Compostela 15782, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Balado
authors.affiliation: Centro de Investigacións Científicas Avanzadas (CICA), Departamento de Química Fundamental, Facultade de Ciencias, Universidade da Coruña , 15071 A Coruña, Spain.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Segade
authors.affiliation: Department of Microbiology and Parasitology, Institute of Aquaculture, Universidade de Santiago de Compostela , Campus Sur, Santiago de Compostela 15782, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Rey
authors.affiliation: Department of Microbiology and Parasitology, Institute of Aquaculture, Universidade de Santiago de Compostela , Campus Sur, Santiago de Compostela 15782, Spain.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Osorio
authors.affiliation: Centro de Investigacións Científicas Avanzadas (CICA), Departamento de Química Fundamental, Facultade de Ciencias, Universidade da Coruña , 15071 A Coruña, Spain.
authors.forename: Jaime
authors.identifier: 0000-0001-5348-6970
authors.initials: J
authors.lastname: Rodríguez
authors.affiliation: Department of Microbiology and Parasitology, Institute of Aquaculture, Universidade de Santiago de Compostela , Campus Sur, Santiago de Compostela 15782, Spain.
authors.forename: Manuel L
authors.identifier: 0000-0001-7964-2089
authors.initials: ML
authors.lastname: Lemos
authors.affiliation: Centro de Investigacións Científicas Avanzadas (CICA), Departamento de Química Fundamental, Facultade de Ciencias, Universidade da Coruña , 15071 A Coruña, Spain.
authors.forename: Carlos
authors.identifier: 0000-0003-2628-303X
authors.initials: C
authors.lastname: Jiménez
mesh_terms: D048409:Aeromonas salmonicida / Q000254:growth & development / Q000378:metabolism*; D005290:Ferric Compounds / Q000737:chemistry*; D007093:Imidazoles / Q000737:chemistry*; D010080:Oxazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D005290:Ferric Compounds; D007093:Imidazoles; D010080:Oxazoles; C091186:acinetobactin