Antimicrobial Potency of Nor-Pyochelin Analogues and Their Cation Complexes against Multidrug-Resistant Pathogens

Area of Science:

• Microbiology
• Medicinal Chemistry
• Biochemistry

Background:

• Pseudomonas aeruginosa is an opportunistic pathogen exhibiting increasing antibiotic resistance.
• Metallophores, such as pyochelin, are crucial virulence factors and regulators in P. aeruginosa.
• Pyochelin, in its iron-bound form (ferripyochelin), regulates pyochelin metabolism via the PchR transcriptional regulator.

Purpose of the Study:

• To design and synthesize nor-pyochelin analogues for tight binding to PchR.
• To investigate the antimicrobial potential of gallium (GaIII) and indium (InIII) complexes with these analogues.
• To evaluate the efficacy of these complexes against multidrug-resistant P. aeruginosa.

Main Methods:

• In silico docking studies to predict ferripyochelin binding sites in PchR.
• Synthesis of selected nor-pyochelin analogues.
• Preparation and antimicrobial testing of GaIII and InIII complexes.
• Assessment of cytotoxicity against mammalian cells.
• Mechanistic studies using transposon mutants.

Main Results:

• GaIII complexes effectively inhibited P. aeruginosa under iron-limited conditions.
• InIII complexes showed greater efficacy in iron-rich environments.
• Several GaIII complexes achieved minimum inhibitory concentrations (MICs) of ≤1 μg/mL against a multidrug-resistant isolate.
• Two InIII systems demonstrated potent activity with an MIC of 8 μg/mL.
• Compounds exhibited low cytotoxicity toward mammalian cells.

Conclusions:

• Nor-pyochelin analogues complexed with GaIII and InIII represent a promising new class of antimicrobials.
• These metal complexes effectively combat multidrug-resistant P. aeruginosa.
• The mechanism of InIII complexes may involve inducing iron deficiency by binding to bacterioferritin.