Synthesis, iron(III) complexation properties, molecular dynamics simulations and P. aeruginosa siderophore-like activity of two pyoverdine analogs

Viviane Antonietti 1 Stéphanie Boudesocque 2 Laurent Dupont 2 Natacha Farvacques 1 Christine Cézard 1 Sophie da Nascimento 1 Jean-François Raimbert 1 Larissa Socrier 3 Thierry-Johann Robin 3 Sandrine Morandat 3 Karim El Kirat 4 Catherine Mullié 1 Pascal Sonnet 1
1 LG2A - Laboratoire de Glycochimie, des antimicrobiens et des agro-ressources
2 ICMR - Institut de Chimie Moléculaire de Reims - UMR 7312
3 GEC - Génie Enzymatique et Cellulaire
4 BMBI - Biomécanique et Bioingénierie
Abstract : P. aeruginosa ranks among the top five organisms causing nosocomial infections. Among the many novel strategies for developing new therapeutics against infection, targeting iron uptake mechanism seems promising as P. aeruginosa needs iron for its growth and survival. To scavenge iron, the bacterium produces siderophores possessing a very high affinity towards Fe(III) ions such as pyoverdines. In this work, we decided to study two pyoverdine analogs, aPvd2 and aPvd3, structurally close to the endogen pyo-verdine. The pFe constants calculated with the values of formation showed a high affinity of aPvd3 towards Fe(III). Molecular dynamics calculations demonstrated that aPvd3-Fe forms with Fe(III) stable 1:1 complexes in water, whereas aPvd2 does not. Only aPvd3 is able to increase the bacterial growth and represents thus an alternative to pyoverdine for iron acquisition by the bacterium. The aPvd2-3 interaction studies with a lipid membrane indicated that they were unable to interact and to cross the plasma membrane of bacteria by passive diffusion. Consequently, the penetration of aPvd3 is ruled by a transport membrane protein. These results showed that aPvd3 may be used to inhibit pyoverdine uptake or to promote the accumulation and release of antibiotics into the cell following a Trojan horse strategy.
Keywords : Trojan horse strategy Iron complexation P. aeruginosa Pyoverdine analogs Siderophores
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Submitted on : Wednesday, January 23, 2019 - 1:55:51 PM
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Viviane Antonietti, Stéphanie Boudesocque, Laurent Dupont, Natacha Farvacques, Christine Cézard, et al.. Synthesis, iron(III) complexation properties, molecular dynamics simulations and P. aeruginosa siderophore-like activity of two pyoverdine analogs. European Journal of Medicinal Chemistry, Elsevier, 2017, 137, pp.338-350. ⟨10.1016/j.ejmech.2017.06.010⟩. ⟨hal-01988822⟩

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