LETTER TO THE EDITOR Chelated iron as an anti-Pseudomonas aeruginosa biofilm therapeutic strategy doi:10.1111/j.1365-2672.2008.03955.x Sir, The article by Musk and Hergenrother demonstrating the effectiveness of iron-saturated iron-chelators directed against Pseudomonas aeruginosa biofilms is intriguing and offers therapeutic hope to individuals with cystic fibrosis (CF) whose lives are foreshortened by infection with this iron-requiring bacterium (Musk and Hergenrother 2008). However, as the authors highlight, there is a lack of appropriate animal models in which to test their findings before potential human studies can be considered. An additional factor is that while the data of Musk and Her- genrother clearly show that high iron concentrations (>50 lmol l )1 ) inhibit biofilm formation, they and others have demonstrated that some iron is required for biofilm formation. The CF lung is already iron replete (median sputum levels c. 50 lmol l )1 ) compared to a lack of iron detectable in normal controls and the high amounts of iron already present may well facilitate P. aeruginosa growth and biofilm formation (Reid et al. 2007). Indeed, a recent paper by Moreau-Marquis et al. (2008) has elo- quently demonstrated intra- and extra-cellular accumula- tion of iron by cultured CF airway epithelial cells and that this directly facilitates P. aeruginosa biofilm forma- tion. Delivering even more iron to the CF lung in a che- lated form in this situation may run the substantial risk of detrimental effects given P. aeruginosa’s very effective and highly adaptable mechanisms of iron acquisition if the concentrations attained in vivo cannot reach the inhibitory levels reached in vitro. A second problem that is intrinsic to any studies of clinical P. aeruginosa isolates is their genetic and phenotypic plasticity. Subculturing several times changes the behaviour of these bacteria very rapidly, especially when grown on iron-depleted culture media. Thus, biofilm forming behaviour and response to iron-saturated chelators in vitro may not be representative of the in vivo response. A further imponderable is whether the effects of additional iron will transform bio- film dwelling and relatively senescent bacteria into plank- tonic living forms of P. aeruginosa with a more virulent phenotype. These issues highlight the need for further research in this area. Nevertheless, Musk and Hergen- rother’s study is the most recent in a body of evidence that suggests iron is important to P. aeruginosa in the clinical setting and not just in CF, and that interfering with bacterial iron homeostatic mechanisms may be a promising therapeutic intervention in many settings, but especially in CF where this bacterium has such a devastating effect. D.W. Reid 1 , C. O’May 1 , L.F. Roddam 1 , I.L. Lamont 2 1 Menzies Research Institute, Hobart, Tasmania, Australia 2 Department of Biochemistry, University of Otago, New Zealand References Moreau-Marquis, S., Bomberger, J.M., Anderson, G.G., Swiatecka-Urban, A., Ye, S., O’Toole, G.A. and Stanton, B.A. (2008) The {Delta}F508-CFTR mutation results in increased biofilm formation by P. aeruginosa by increasing iron availability. Am J Physiol Lung Cell Mol Physiol 295, L25–37. Musk, D.J., Jr and Hergenrother, P.J. (2008) Chelated iron sources are inhibitors of Pseudomonas aeruginosa biofilms and distribute efficiently in an in vitro model of drug delivery to the human lung. J Appl Microbiol 105, 380–388. Reid, D.W., Carroll, V., O’May, C., Champion, A. and Kirov, S.M. (2007) Increased airway iron as a potential factor in the persistence of Pseudomonas aeruginosa infection in cystic fibrosis. Eur Respir J 30, 286–292. Journal of Applied Microbiology ISSN 0266-8254 1058 Journal compilation ª 2009 The Society for Applied Microbiology, Journal of Applied Microbiology 106 (2009) 1058 ª 2009 The Authors