Chelated iron sources are inhibitors ofPseudomonas aeruginosabiofilms and distribute efficiently in anin vitromodel of drug delivery to the human lung

Abstract

Aims: To determine whether chelated sources of ferric iron were efficient inhibitors of biofilm formation in Pseudomonas aeruginosa and might be suitable for drug delivery to the lungs of cystic fibrosis (CF) patients via nebulization. Methods and Results: The response of P. aeruginosa biofilms to elevated iron concentrations in the form of eight structurally varied iron chelators in a microtitre plate assay for biofilm production was examined in the lab. Among these iron chelates, picolinic acid and acetohydroxamic acid‐chelated iron were able to effectively thwart biofilm production in P. aeruginosa PA14 and in 20 clinical isolates of P. aeruginosa from a local hospital. The chelated iron sources showed excellent distribution in an Anderson cascade impactor model of particle size distribution in the human lung. Conclusions: Ferric picolinate and ferric acetohydroxamate are effective anti‐biofilm compounds against both lab and clinical strains of P. aeruginosa and are readily nebulized into particles of suitable size for lung delivery. Significance and Impact of the Study: The data herein serve both to solidify the growing base of literature correlating high iron levels with biofilm inhibition in P. aeruginosa and to highlight the potential of these chelators as nebulized agents to combat biofilms of P. aeruginosa in CF patients.

Iron acquisition by Pseudomonas aeruginosa in the lungs of patients with cystic fibrosis

“…These data, demonstrating the need for siderophore-mediated iron transport in normal biofilm development, are consistent with earlier findings that iron sequestration by lactoferrin inhibits P. aeruginosa biofilm development and affects twitching motility that is essential for biofilm development (Singh et al 2002). Conversely, high amounts of iron also inhibit biofilm formation (Musk et al 2005;Yang et al 2007;Musk and Hergenrother 2008). P. aeruginosa has the capacity to use a wide range of siderophores synthesized by other organisms (reviewed in Cornelis and Matthijs 2002;Poole and McKay 2003) and has at least two systems for uptake of heme (Ochsner et al 2000).…”

Tobramycin and FDA-Approved Iron Chelators Eliminate Pseudomonas aeruginosa Biofilms on Cystic Fibrosis Cells

“…Although DSX reduces P. aeruginosa CFU when added to either the apical or basolateral side of CFBE cells (in combination with tobramycin), DSX is more effective when added to the apical side of airway cells. Interestingly, DFO has recently been shown to be a good candidate for nebulization, as it distributed efficiently in a model of the human lung (47). Thus, clinically, nebulization of tobramyin with DFO might be an effective way to eliminate established P. aerginosa biofilms in patients with CF.…”

Targeting iron uptake to controlPseudomonas aeruginosainfections in cystic fibrosis

“…Similarly, in vitro studies suggest iron chelators delivered directly to biofilms grown on the apical membrane of CFBE cells inhibit growth more effectively than when they are applied to the basal membrane, suggesting that direct delivery to the airway may also be the preferred mode of delivery for these compounds [76]. The possibility of localised delivery of chelators is supported by in vitro modelling, which has suggested that chelated iron may be effectively aerosolised to a particle size suitable for lung delivery [61].…”

“…Delivering toxic amounts of iron to P. aeruginosa In vitro studies have suggested that iron-laden synthetic chelators can be utilised to deliver high concentrations of iron to biofilm-dwelling P. aeruginosa with resultant biofilm disruption [61]. While this approach demonstrates promise in vitro, the high redox activity of iron and potential for harmful reactive oxygen species generation within the human airway must be considered.…”