Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ahuja IS, Singh R, Sriramulu R (1979) Structural information on zinc(II) and cadmium(II) acetate complexes with nicotinic acid and related ligands from their infrared spectra. J Mol Struct 53:301–304. https://doi.org/10.1016/0022-2860(79)80353-1
Bax A, Davis DG (1985) Practical aspects of two-dimensional transverse NOE spectroscopy. J Magn Reson 1969 63:207–213. https://doi.org/10.1016/0022-2364(85)90171-4
Becke AD (1993) A new mixing of Hartree-Fock and local density-functional theories. J Chem Phys. https://doi.org/10.1063/1.464304
Bennison LR, Miller CN, Summers RJ et al (2017) The pH of wounds during healing and infection: a descriptive literature review. Wound Pract Res 25:63–69
Blair JMA, Bavro VN, Ricci V et al (2015) AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity. Proc Natl Acad Sci USA 112:3511–3516. https://doi.org/10.1073/pnas.1419939112
Braun V, Hantke K (2013) The tricky ways bacteria cope with iron limitation. In: Chakraborty R, Braun V, Hantke K, Cornelis P (eds) Iron uptake in bacteria with emphasis on E. coli and Pseudomonas. Springer, Dordrecht, pp 31–66
Brown ED, Wright GD (2016) Antibacterial drug discovery in the resistance era. Nature 529:336–343. https://doi.org/10.1038/nature17042
Bruker Corporation (2012) Almanac | Analytical Chemistry | Nuclear Magnetic Resonance
Cama J, Bajaj H, Pagliara S et al (2015) Quantification of fluoroquinolone uptake through the outer membrane channel OmpF of Escherichia coli. J Am Chem Soc 137:13836–13843. https://doi.org/10.1021/jacs.5b08960
ChemAxon (2015a) MarvinSketch. ChemAxon
ChemAxon (2015b) Calculator Plugins. ChemAxon
Cobessi D, Celia H, Pattus F (2005) Crystal structure at high resolution of ferric-pyochelin and its membrane receptor FptA from Pseudomonas aeruginosa. J Mol Biol 352:893–904. https://doi.org/10.1016/j.jmb.2005.08.004
Covington AK, Paabo M, Robinson RA, Bates RG (1968) Use of the glass electrode in deuterium oxide and the relation between the standardized pD (paD) scale and the operational pH in heavy water. Anal Chem 40:700–706. https://doi.org/10.1021/ac60260a013
Delaglio F (2012) Dynamo: the NMR molecular dynamics and analysis system. http://spin.niddk.nih.gov/NMRPipe/dynamo
Deshpande AD, Baheti KG, Chatterjee NR (2004) Degradation of β-lactam antibiotics. Curr Sci 87:12
Drawz SM, Bonomo RA (2010) Three decades of β-lactamase inhibitors. Clin Microbiol Rev 23:160–201. https://doi.org/10.1128/CMR.00037-09
Ferguson AD, Hofmann E, Coulton JW et al (1998) Siderophore-mediated iron transport: crystal structure of FhuA with bound lipopolysaccharide. Science 282:2215–2220
Fernandez L, Hancock REW (2012) Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance. Clin Microbiol Rev 25:661–681
Frisch M, Trucks G, Schlegel H et al (2009) Gaussian 09, Revision A.02. Gaussian, Inc., Wallingford (CT)
Harrington JM, Gootz T, Flanagan M et al (2012) Characterization of the aqueous iron(III) chelation chemistry of a potential Trojan Horse antimicrobial agent: chelate structure, stability and pH dependent speciation. Biometals 25:1023–1036. https://doi.org/10.1007/s10534-012-9568-0
Ito A, Sato T, Ota M et al (2018) In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against gram-negative bacteria. Antimicrob Agents Chemother 62:e01454-17. https://doi.org/10.1128/AAC.01454-17
Jacobsen NE (2007) NMR spectroscopy explained. John Wiley & Sons Inc, Hoboken
Jones RO, Gunnarsson O (1989) The density functional formalism, its applications and prospects. Rev Mod Phys 61:689. https://doi.org/10.1103/RevModPhys.61.689
Katsube T, Echols R, Arjona Ferreira JC et al (2017) Cefiderocol, a siderophore cephalosporin for gram-negative bacterial infections: pharmacokinetics and safety in subjects with renal impairment. J Clin Pharmacol 57:584–591. https://doi.org/10.1002/jcph.841
Lachowicz JI, Nurchi VM, Crisponi G et al (2016) Hydroxypyridinones with enhanced iron chelating properties. Synthesis, characterization and in vivo tests of 5-hydroxy-2-(hydroxymethyl)pyridine-4(1H)-one. Dalton Trans 45:6517–6528. https://doi.org/10.1039/C6DT00129G
Loftsson T (2014) Drug stability for pharmaceutical scientists. Elsevier, New York
Mach T, Neves P, Spiga E et al (2008) Facilitated permeation of antibiotics across membrane channels–interaction of the quinolone moxifloxacin with the OmpF channel. J Am Chem Soc 130:13301–13309. https://doi.org/10.1021/ja803188c
Mahendran KR, Hajjar E, Mach T et al (2010) Molecular basis of enrofloxacin translocation through OmpF, an outer membrane channel of Escherichia coli—when binding does not imply translocation. J Phys Chem B 114:5170–5179. https://doi.org/10.1021/jp911485k
Malloci G, Vargiu AV, Serra G et al (2015) A database of force-field parameters, dynamics, and properties of antimicrobial compounds. Molecules 20:13997–14021. https://doi.org/10.3390/molecules200813997
Matzanke BF (2006) Iron transport: siderophores. In: Encyclopedia of inorganic chemistry. John Wiley & Sons, Ltd, New York
Moynié L, Luscher A, Rolo D et al (2017) Structure and function of the PiuA and PirA siderophore-drug receptors from Pseudomonas aeruginosa and Acinetobacter baumannii. Antimicrob Agents Chemother 61:e02531-16. https://doi.org/10.1128/AAC.02531-16
Nikaido H (1994) Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science 264:382–388
O’Shea R, Moser HE (2008) Physicochemical properties of antibacterial compounds: implications for drug discovery. J Med Chem 51:2871–2878. https://doi.org/10.1021/jm700967e
Oostenbrink C, Villa A, Mark AE, van Gunsteren WF (2004) A biomolecular force field based on the free enthalpy of hydration and solvation: the GROMOS force-field parameter sets 53A5 and 53A6. J Comput Chem 25:1656–1676. https://doi.org/10.1002/jcc.20090
Page MGP (2013) Siderophore conjugates. Ann N Y Acad Sci 1277:115–126. https://doi.org/10.1111/nyas.12024
Page MGP, Dantier C, Desarbre E (2010) In vitro properties of BAL30072, a novel siderophore sulfactam with activity against multiresistant gram-negative bacilli. Antimicrob Agents Chemother 54:2291–2302. https://doi.org/10.1128/AAC.01525-09
Pagès J-M, James CE, Winterhalter M (2008) The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria. Nat Rev Microbiol 6:893–903. https://doi.org/10.1038/nrmicro1994
Peuckert F, Ramos-Vega AL, Miethke M et al (2011) The siderophore binding protein FeuA shows limited promiscuity toward exogenous triscatecholates. Chem Biol 18:907–919. https://doi.org/10.1016/j.chembiol.2011.05.006
Santos AM (2002) Hydroxypyridinone complexes with aluminium. In vitro/vivo studies and perspectives. Coord Chem Rev 228:187–203. https://doi.org/10.1016/S0010-8545(02)00035-8
Schüttelkopf AW, van Aalten DMF (2004) PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr 60:1355–1363. https://doi.org/10.1107/S0907444904011679
Smith BC (1999) Infrared spectral interpretation: a systematic approach. CRC Press, Boca Raton
Stavenger RA, Winterhalter M (2014) TRANSLOCATION project: how to get good drugs into bad bugs. Sci Transl Med 6:22. https://doi.org/10.1126/scitranslmed.3008605
Stephens P, Devlin F, Chabalowski C, Frisch M (1994) Ab-initio calculation of vibrational absorption and circular-dichroism spectra using density-functional force-fields. J Phys Chem 98:11623–11627
Tomasi J, Mennucci B, Cammi R (2005) Quantum mechanical continuum solvation models. Chem Rev 105:2999–3094. https://doi.org/10.1021/cr9904009
Tommasi R, Brown DG, Walkup GK et al (2015) ESKAPEing the labyrinth of antibacterial discovery. Nat Rev Drug Discov 14:529–542. https://doi.org/10.1038/nrd4572
Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461. https://doi.org/10.1002/jcc.21334
The PEW Charitable Trusts (2018) Antibiotics currently in clinical development. http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-development
van Eldik R, Harvey J (2010) Theoretical and computational inorganic chemistry. Academic Press, Cambridge
Weaver KD, Heymann JJ, Mehta A et al (2008) Ga3 + as a mechanistic probe in Fe3 + transport: characterization of Ga3 + interaction with FbpA. J Biol Inorg Chem JBIC Publ Soc Biol Inorg Chem 13:887–898. https://doi.org/10.1007/s00775-008-0376-5
Webb B, Sali A (2014) Protein structure modeling with MODELLER. In: Protein structure prediction. Humana Press, New York, pp 1–15
WHO (2014) Antimicrobial resistance: global report on surveillance. World Health Organization, Geneva
Wilde EJ, Hughes A, Blagova EV et al (2017) Interactions of the periplasmic binding protein CeuE with Fe(III) n-LICAM(4-) siderophore analogues of varied linker length. Sci Rep 7:45941. https://doi.org/10.1038/srep45941
Wilson BR, Bogdan AR, Miyazawa M et al (2016) Siderophores in iron metabolism: from mechanism to therapy potential. Trends Mol Med 22:1077–1090. https://doi.org/10.1016/j.molmed.2016.10.005
Yamaji T, Saito T, Hayamizu K, et al SDBSWeb: https://sdbs.db.aist.go.jp (National Institute of Advanced Industrial Science and Technology)
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
Eric Desarbre is employee of Basilea Pharmaceutica International Ltd. Malcolm Page is employee and owns stock of Basilea Pharmaceutica International Ltd.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Scorciapino, M.A., Malloci, G., Serra, I. et al. Complexes formed by the siderophore-based monosulfactam antibiotic BAL30072 and their interaction with the outer membrane receptor PiuA of P. aeruginosa. Biometals 32, 155–170 (2019). https://doi.org/10.1007/s10534-018-00166-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10534-018-00166-0