Complexes formed by the siderophore-based monosulfactam antibiotic BAL30072 and their interaction with the outer membrane receptor PiuA of P. aeruginosa
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Nuclear magnetic resonance and infrared spectroscopy have been used to investigate the formation of complexes of BAL30072 with Fe3+ and Ga3+ in solution and to collect geometrical parameters supporting reliable 3D structure models. Structural models for the ligand–metal complexes with different stoichiometries have been characterized using density functional theory calculations. Blind ensemble docking to the PiuA receptor from P. aeruginosa was performed for the different complexes to compare binding affinities and statistics of the residues most frequently contacted. When compared to analogues, BAL30072 was found to have an intrinsic propensity to form complexes with low ligand-to-metal stoichiometry. By using one of the sulfate oxygen atoms as a third donor in addition to the bidentate pyridinone moiety, BAL30072 can form a L2M complex, which was predicted to be the one with the best binding affinity to PiuA. The example of BAL30072 strongly suggests that a lower stoichiometry might be the one recognized by the receptor, so that to focus only on the highest stoichiometry might be misleading for siderophores with less than six donors.
KeywordsNuclear magnetic resonance Molecular docking Infrared spectroscopy Antibiotic resistance
The research leading to these results was conducted as part of the Translocation consortium (www.translocation.eu) and has received support from the Innovative Medicines Initiatives Joint Undertaking under Grant Agreement Nr. 115525, resources which are composed of financial contribution from the European Union’s seventh framework programme (FP7/2007-2013) and EFPIA companies in kind contribution. M.C. thanks the project RAS/FdS (CUP F72F16003070002). Prof. Mariano Casu, Dept. of Physics, University of Cagliari, is kindly acknowledged for the NMR time and the fruitful discussions.
Compliance with ethical standards
Conflict of interest
Eric Desarbre is employee of Basilea Pharmaceutica International Ltd. Malcolm Page is employee and owns stock of Basilea Pharmaceutica International Ltd.
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