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Iron chelation directed against biofilms as an adjunct to conventional antibiotics

2009; American Physical Society; Volume: 296; Issue: 5 Linguagem: Inglês

10.1152/ajplung.00058.2009

1522-1504

David W. Reid, C O'May, Sylvia M. Kirov, Louise F. Roddam, Iain L. Lamont, Kevin Sanderson,

Cystic Fibrosis Research Advances

LETTER TO THE EDITORIron chelation directed against biofilms as an adjunct to conventional antibioticsD. W. Reid, C. O'May, S. M. Kirov, L. Roddam, I. L. Lamont, and K. SandersonD. W. Reid, C. O'May, S. M. Kirov, L. Roddam, I. L. Lamont, andK. SandersonPublished Online:01 May 2009https://doi.org/10.1152/ajplung.00058.2009MoreSectionsPDF (314 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat to the editor: We read with interest the study by Moreau-Marquis et al. demonstrating the bactericidal effect of two iron-chelating compounds directed against Pseudomonas aeruginosa when combined with the aminoglycoside antibiotic tobramycin, following their recent demonstration of abnormal cystic fibrosis epithelial cell iron hardling (1, 2). In similar experiments to those of Moreau-Marquis and colleagues, we assessed the effects of the synthetic iron chelator 2,2-dipyridyl (2DP) on minimal inhibitory concentrations (MICs) of ceftazidime and meropenem. We used a broth microdilution technique in medium containing low (≤1 μM) or high (10 μM) amounts of iron (FeCl3) and examined growth and biofilm formation under aerobic and anaerobic conditions. The inclusion of anaerobic experiments is critical, as these conditions are likely encountered by P. aeruginosa in the cystic fibrosis (CF) lung environment, and anaerobic growth within biofilms is thought to be a critical factor in persistence (4, 5). Our data demonstrate that the iron requirement for growth and biofilm formation is much higher when bacteria are grown anaerobically compared with aerobically (O'May, unpublished observations). Under aerobic conditions, iron had little effect on MICs, but when P. aeruginosa strains were grown anaerobically in the presence of supplemental iron, the MICs were significantly increased to the point where the strains were considered to be resistant. The antimicrobial resistance of strains to ceftazidime and meropenem was significantly decreased (up to 4-fold) under both aerobic and anaerobic growth conditions by the addition of 2DP at levels that did not inhibit P. aeruginosa growth. Interestingly, under anaerobic conditions, the concentration of 2DP required to achieve the same reduction in MIC was much lower than under aerobic conditions.In experiments using a flow cell biofilm model in which bacteria were grown on glass surfaces and stained for viability (live P. aeruginosa stains green and dead bacteria stain red; BacLight), we have demonstrated that a combination of 2DP and tobramycin results in areas of denuded biofilm in close proximity to dead bacteria (see Fig. 1). In contrast, tobramycin on its own had no effect. The 2DP and tobramycin combination was superior to 2DP alone. We have previously reported, using this model, that 2DP can reduce P. aeruginosa biofilm mass and height, but not bacterial viability or biofilm surface area coverage (chelator added to mature biofilms formed over 2–3 days) (O'May, unpublished observations). Our flow cell experiments imply that iron-chelation disrupts biofilm structure, which then allows antibiotic penetration and bacterial killing. In the flow cell method, biofilms are mature and in their most resistant form when chelator-antibiotic interventions are introduced and complement the results from the model of Moreau-Marquis and colleagues where biofilms were assessed at an early stage of development (≤6 h).Collectively, the data of our studies (3) and those of Moreau-Marquis et al. (1) show that combination therapy with iron-chelators and conventional antibiotics may be particularly effective in the CF lung, especially in view of the increased amounts of iron available to support P. aeruginosa replication and biofilm formation in this disease. Our data also suggest that iron chelation may enhance the efficacy of antibiotics such as tobramycin under low oxygen tensions, which normally impair the bactericidal effects of the aminoglycosides. Fig. 1.2,2-Dipyridyl (2DP, 2,500 μM) was added to the flow cell from day 3 once the biofilm had become established. Flow cells were exposed to tobramycin (100 μg/ml) for 1 h on day 7 and then stained for viability. Five representative panels are shown for each treatment. A: tobramycin alone; B: 2DP alone; C: tobramycin + 2DP. Live bacteria stain green and dead bacteria stain red. Yellow represents regions where both live and dead bacteria are present, and darker areas show where no biofilm is present. The images for control experiments are not shown.Download figureDownload PowerPointREFERENCES1 Moreau-Marquis S, Bomberger JM, Anderson GG, Swiatecka-Urban A, Ye S, O'Toole GA, Stanton BA. The DeltaF508-CFTR mutation results in increased biofilm formation by Pseudomonas aeruginosa by increasing iron availability. Am J Physiol Lung Cell Mol Physiol 295: L25–L37, 2008.Link | ISI | Google Scholar2 Moreau-Marquis S, O'Toole GA, Stanton BA. Tobramycin and FDA-approved iron chelators eliminate P. aeruginosa biofilms on cystic fibrosis cells. Am J Respir Cell Mol Biol. In press.Google Scholar3 Reid DW, Carroll V, O'May C, Champion A, Kirov SM. Increased airway iron as a potential factor in the persistence of Pseudomonas aeruginosa infection in cystic fibrosis. Eur Respir J 30: 286–292, 2007.Crossref | PubMed | ISI | Google Scholar4 Worlitzsch D, Tarran R, Ulrich M, Schwab U, Cekici A, Meyer KC, Birrer P, Bellon G, Berger J, Weiss T, Botzenhart K, Yankaskas JR, Randell S, Boucher RC, Doring G. Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J Clin Invest 109: 317–325, 2002.Crossref | PubMed | ISI | Google Scholar5 Yoon SS, Hennigan RF, Hilliard GM, Ochsner UA, Parvatiyar K, Kamani MC, Allen HL, DeKievit TR, Gardner PR, Schwab U, Rowe JJ, Iglewski BH, McDermott TR, Mason RP, Wozniak DJ, Hancock RE, Parsek MR, Noah TL, Boucher RC, Hassett DJ. Pseudomonas aeruginosa anaerobic respiration in biofilms: relationships to cystic fibrosis pathogenesis. Dev Cell 3: 593–603, 2002.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: D. W. Reid, Menzies Research Institute, Dept. of Pathology, Univ. of Tasmania, Hobart, Tasmania, 7001 Australia (e-mail: [email protected]) Download PDF Previous Back to Top FiguresReferencesRelatedInformation Cited ByFighting microbial pathogens by integrating host ecosystem interactions and evolution30 December 2020 | BioEssays, Vol. 43, No. 3Tuning the Anti(myco)bacterial Activity of 3-Hydroxy-4-pyridinone Chelators through Fluorophores20 October 2018 | Pharmaceuticals, Vol. 11, No. 4Antibiofilm activity of (1)-N-2-methoxybenzyl-1,10-phenanthrolinium bromide against Candida albicansJournal de Mycologie Médicale, Vol. 28, No. 2Study of the effect of thiourea and N-ethyl groups on antibacterial activity of rhodamine-labeled 3,4-HPO iron chelators against Gram (+/−) bacteria12 March 2018 | Medicinal Chemistry Research, Vol. 27, No. 5Staphylococcus epidermidis is largely dependent on iron availability to form biofilmsInternational Journal of Medical Microbiology, Vol. 307, No. 8Review on bacterial biofilm: An universal cause of contaminationBiocatalysis and Agricultural Biotechnology, Vol. 7The 'liaisons dangereuses' between iron and antibiotics4 March 2016 | FEMS Microbiology Reviews, Vol. 40, No. 3Biofilm, pathogenesis and prevention—a journey to break the wall: a review16 September 2015 | Archives of Microbiology, Vol. 198, No. 1Evaluation of Gallium Citrate Formulations against a Multidrug-Resistant Strain of Klebsiella pneumoniae in a Murine Wound Model of InfectionAntimicrobial Agents and Chemotherapy, Vol. 59, No. 10Lactoferrin and Cystic Fibrosis Airway InfectionApplying insights from biofilm biology to drug development — can a new approach be developed?1 October 2013 | Nature Reviews Drug Discovery, Vol. 12, No. 10Hacking into bacterial biofilms: a new therapeutic challenge13 June 2011 | Annals of Intensive Care, Vol. 1, No. 1 More from this issue > Volume 296Issue 5May 2009Pages L857-L858 Copyright & PermissionsCopyright © 2009 the American Physiological Societyhttps://doi.org/10.1152/ajplung.00058.2009PubMed19401520History Published online 1 May 2009 Published in print 1 May 2009 Metrics