Biofilm-specific uptake of a 4-pyridone-based iron chelator by Pseudomonas aeruginosa

Abstract

Iron is an essential nutrient for virtually all microbes and limiting the concentration of available iron is a potential strategy to be used as an alternative to antibiotic treatment. In this study we analysed the antimicrobial activity of two chelators, specifically 3-hydroxy-1,2-dimethyl-4(1H)-pyridone (deferiprone, DFP), which is clinically approved for the treatment of iron overload disorders, and its 1,2-diethyl homologue, CP94. Both compounds showed moderate activity towards planktonically growing P. aeruginosa cells, and the mechanism of action of these chelators was indeed by limiting the amount of free iron. Surprisingly, the compounds behaved very differently when the cells were grown in biofilms. DFP also showed inhibitory effects on biofilm formation but in contrast, CP94 stimulated this process, in particular at high concentrations. We hypothesised that CP94 behaves as an iron carrier, which was confirmed by our observation that it had antimicrobial synergy with the toxic metals, gallium and copper. This suggests that P. aeruginosa produces a biofilm-specific transport protein that recognises CP94 but not the closely related compound DFP.

The Iron Chelator, DIBI, Reduces Bacterial Load and Inflammation in Experimental Lung Infection

“…Consistently, it has been demonstrated that other iron chelators have the potential ability to combat P. aeruginosa biofilms. For example, Sharareh et al found that deferiprone (DFP) can be inhibitory to growth of P. aeruginosa with high concentration [20]. Similarly, gallium is also under consideration as an anti-pseudomonal agent, because it can inhibit P. aeruginosa growth and biofilm formation by disrupting bacterial iron homeostasis [21].…”

Potential additional effects of iron chelators on antimicrobial- impregnated central venous catheters

“…Iron-chelation therapy has been tested in P. aeruginosa to explore adjunctive therapy for chronic P. aeruginosa infection. Deferiprone, a synthetic iron chelator, has been shown to inhibit biofilm formation (Houshmandyar et al, 2021 ). Furthermore, the combination of iron chelators and antimicrobial agents has shown enhanced biofilm inhibitory activity; examples include combination therapy with the iron (VI) chelator N, N'-bis (2-hydroxybenzyl) ethylenediamine-N, N'-diacetic acid and colistin in an in vitro experiment (Mettrick et al, 2020 ), and with the iron chelators deferoxamine or deferasirox and tobramycin (Moreau-Marquis et al, 2009 ).…”

Deferiprone-Gallium-Protoporphyrin Chitogel Decreases Pseudomonas aeruginosa Biofilm Infection without Impairing Wound Healing

“…This approach capitalises on the intricate iron dynamics within P. aeruginosa, offering a promising avenue for disrupting biofilm development in clinical settings. Def reduces iron availability by forming a complex with free iron at a ratio of 3:1, with three Def molecules to one iron [22].…”