Synthesis, iron(III) complexation properties, molecular dynamics simulations and P. aeruginosa siderophore-like...

Area of Science:

• Microbiology and Infectious Diseases
• Biochemistry and Molecular Biology
• Drug Discovery and Development

Background:

• Pseudomonas aeruginosa is a major cause of hospital-acquired infections.
• Iron acquisition is crucial for P. aeruginosa survival and growth.
• Siderophores, like pyoverdine, are high-affinity iron chelators produced by bacteria.

Purpose of the Study:

• To investigate two pyoverdine analogs, aPvd2 and aPvd3, as potential therapeutic agents against P. aeruginosa.
• To evaluate their iron-binding affinity, stability, and interaction with bacterial membranes.
• To explore their utility in novel anti-infective strategies.

Main Methods:

• Calculation of pFe constants to determine iron-binding affinity.
• Molecular dynamics simulations to assess complex stability.
• Bacterial growth assays to evaluate iron acquisition efficacy.
• Lipid membrane interaction studies to predict membrane permeability.

Main Results:

• aPvd3 exhibited high affinity and formed stable Fe(III) complexes, unlike aPvd2.
• aPvd3 promoted bacterial growth, indicating its role in iron acquisition.
• Neither analog could cross the bacterial plasma membrane via passive diffusion; aPvd3 likely uses a transport protein.

Conclusions:

• aPvd3 is a promising alternative to pyoverdine for iron acquisition by P. aeruginosa.
• aPvd3's mechanism suggests potential applications in inhibiting pyoverdine uptake.
• aPvd3 could be utilized in a Trojan horse strategy to enhance antibiotic delivery into bacterial cells.