Cationic Peptides Facilitate Iron-induced Mutagenesis in Bacteria

English version České info

Cationic antimicrobial peptides (cAMPs) are small proteins naturally produced by the immune system to limit bacterial growth mainly through pore formation in the membrane. It has recently been suggested that sub-inhibitory concentrations of cAMPs promote bacterial mutagenesis, similarly to antibiotics. However, we previously reported that cAMPs do not increase mutation rate and do not activate bacterial stress responses. Here we resolve this contradiction. We report that free iron in the culture medium increases mutagenesis in the presence of cAMPs. We show that sub-inhibitory concentrations of cAMPs facilitate entry of free iron into bacterial cells, where it interacts with hydrogen peroxide, thereby resulting in production of DNA-damaging reactive oxygen species and increased mutagenesis. Moreover, these results may have clinically-relevant implications: while very little free iron is normally present in healthy individuals, this is not the case in patients suffering from cystic fibrosis, where elevated bacterial mutagenesis promotes antibiotic resistance and contributes to persistence and severity of infection. Thus, an intervention aimed at reduction of free iron in the lungs could reduce the cAMPs-facilitation of iron-mediated mutagenesis; hence antibiotic resistance and pathoadaptation.

Vyšlo v časopise: Cationic Peptides Facilitate Iron-induced Mutagenesis in Bacteria. PLoS Genet 11(10): e32767. doi:10.1371/journal.pgen.1005546
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005546

Souhrn

Zdroje

1. Stover CK, Pham XQ, Erwin AL, Mizoguchi SD, Warrener P, Hickey MJ, et al. Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature. 2000/09/13 ed. 2000;406: 959–964. doi: 10.1038/35023079 10984043

2. Hassett DJ, Korfhagen TR, Irvin RT, Schurr MJ, Sauer K, Lau GW, et al. Pseudomonas aeruginosa biofilm infections in cystic fibrosis: insights into pathogenic processes and treatment strategies. Expert Opin Ther Targets. 2010/01/09 ed. 2010;14: 117–130. doi: 10.1517/14728220903454988 20055712

3. Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis. 2002;34: 634–40. doi: 10.1086/338782 11823954

4. Rodríguez-Rojas A, Oliver A, Blázquez J. Intrinsic and environmental mutagenesis drive diversification and persistence of Pseudomonas aeruginosa in chronic lung infections. J Infect Dis. 2012;205: 121–7. doi: 10.1093/infdis/jir690 22080096

5. Oliver A, Canton R, Campo P, Baquero F, Blazquez J. High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. Science (80-). 2000/05/20 ed. 2000;288: 1251–1254. 8507 [pii]

6. Limoli DH, Rockel AB, Host KM, Jha A, Kopp BT, Hollis T, et al. Cationic antimicrobial peptides promote microbial mutagenesis and pathoadaptation in chronic infections. Ausubel FM. PLoS Pathog. Public Library of Science; 2014;10: e1004083. doi: 10.1371/journal.ppat.1004083 24763694

7. Rodríguez-Rojas A, Makarova O, Rolff J. Antimicrobials, stress and mutagenesis. PLoS Pathog. 2014;10: e1004445. doi: 10.1371/journal.ppat.1004445 25299705

8. Miller JH. Experiments in molecular genetics [Internet]. Cold Spring Harbor Laboratory; 1972. Available: http://books.google.co.uk/books/about/Experiments_in_molecular_genetics.html?id=PtVpAAAAMAAJ&pgis=1

9. Abdul-Tehrani H, Hudson AJ, Chang YS, Timms AR, Hawkins C, Williams JM, et al. Ferritin mutants of Escherichia coli are iron deficient and growth impaired, and fur mutants are iron deficient. J Bacteriol. 1999;181: 1415–28. Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=93529&tool=pmcentrez&rendertype=abstract 10049371

10. Yang Y, Harris DP, Luo F, Xiong W, Joachimiak M, Wu L, et al. Snapshot of iron response in Shewanella oneidensis by gene network reconstruction. BMC Genomics. 2009;10: 131. doi: 10.1186/1471-2164-10-131 19321007

11. Girardello R, Bispo PJM, Yamanaka TM, Gales AC. Cation concentration variability of four distinct Mueller-Hinton agar brands influences polymyxin B susceptibility results. J Clin Microbiol. 2012;50: 2414–8. doi: 10.1128/JCM.06686-11 22553247

12. Imlay J, Chin S, Linn S. Toxic DNA damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro. Science (80-). 1988;240: 640–642. doi: 10.1126/science.2834821

13. Andrews SC, Robinson AK, Rodríguez-Quiñones F. Bacterial iron homeostasis. FEMS Microbiol Rev. 2003;27: 215–37. Available: http://www.ncbi.nlm.nih.gov/pubmed/12829269 12829269

14. Yamamoto Y, Fukui K, Koujin N, Ohya H, Kimura K, Kamio Y. Regulation of the intracellular free iron pool by Dpr provides oxygen tolerance to Streptococcus mutans. J Bacteriol. 2004;186: 5997–6002. doi: 10.1128/JB.186.18.5997–6002.2004 15342568

15. 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. 2007;30: 286–92. doi: 10.1183/09031936.00154006 17504792

16. 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. 2007/05/17 ed. 2007;30: 286–292. 09031936.00154006 [pii] doi: 10.1183/09031936.00154006 17504792

17. Worlitzsch D, Tarran R, Ulrich M, Schwab U, Cekici A, Meyer KC, et al. Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J Clin Invest. 2002/02/06 ed. 2002;109: 317–325. doi: 10.1172/JCI13870 11827991

18. Zasloff M. Antimicrobial peptides of multicellular organisms. Nature. 2002;415: 389–95. doi: 10.1038/415389a 11807545

19. Ratledge C, Dover LG. Iron metabolism in pathogenic bacteria. Annu Rev Microbiol. Annual Reviews 4139 El Camino Way, P.O. Box 10139, Palo Alto, CA 94303–0139, USA; 2000;54: 881–941. doi: 10.1146/annurev.micro.54.1.881 11018148

20. Nasnas R, Saliba G, Hallak P. [The revival of colistin: an old antibiotic for the 21st century]. Pathol Biol. 2008/01/08 ed. 2009;57: 229–235. S0369-8114(07)00223-4 [pii] doi: 10.1016/j.patbio.2007.09.013

21. Biswas S, Brunel J-M, Dubus J-C, Reynaud-Gaubert M, Rolain J-M. Colistin: an update on the antibiotic of the 21st century. Expert Rev Anti Infect Ther. 2012;10: 917–34. doi: 10.1586/eri.12.78 23030331

22. Colistin: An Update on the Antibiotic of the 21st Century [Internet]. [cited 27 Aug 2015]. Available: http://www.medscape.com/viewarticle/772588_6

23. Hunter RC, Asfour F, Dingemans J, Osuna BL, Samad T, Malfroot A, et al. Ferrous iron is a significant component of bioavailable iron in cystic fibrosis airways. MBio. 2013;4: e00557–13–. doi: 10.1128/mBio.00557-13 23963183

24. Kreamer NN, Costa F, Newman DK. The ferrous iron-responsive BqsRS two-component system activates genes that promote cationic stress tolerance. MBio. 2015;6: e02549. doi: 10.1128/mBio.02549-14 25714721

25. Méhi O, Bogos B, Csörgő B, Pál F, Nyerges A, Papp B, et al. Perturbation of iron homeostasis promotes the evolution of antibiotic resistance. Mol Biol Evol. 2014;31: 2793–804. doi: 10.1093/molbev/msu223 25063442

26. Wenzel M, Chiriac AI, Otto A, Zweytick D, May C, Schumacher C, et al. Small cationic antimicrobial peptides delocalize peripheral membrane proteins. Proc Natl Acad Sci U S A. 2014;111: E1409–18. doi: 10.1073/pnas.1319900111 24706874

27. Goldman MJ, Anderson GM, Stolzenberg ED, Kari UP, Zasloff M, Wilson JM. Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell. 1997;88: 553–60. Available: http://www.ncbi.nlm.nih.gov/pubmed/9038346 9038346

28. McPhee JB, Bains M, Winsor G, Lewenza S, Kwasnicka A, Brazas MD, et al. Contribution of the PhoP-PhoQ and PmrA-PmrB two-component regulatory systems to Mg2+-induced gene regulation in Pseudomonas aeruginosa. J Bacteriol. 2006/05/19 ed. 2006;188: 3995–4006. 188/11/3995 [pii] doi: 10.1128/JB.00053-06 16707691

29. Moskowitz SM, Ernst RK, Miller SI. PmrAB, a two-component regulatory system of Pseudomonas aeruginosa that modulates resistance to cationic antimicrobial peptides and addition of aminoarabinose to lipid A. J Bacteriol. 2004;186: 575–9. Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=305751&tool=pmcentrez&rendertype=abstract 14702327

30. Marlovits TC, Haase W, Herrmann C, Aller SG, Unger VM. The membrane protein FeoB contains an intramolecular G protein essential for Fe(II) uptake in bacteria. Proc Natl Acad Sci U S A. 2002;99: 16243–8. doi: 10.1073/pnas.242338299 12446835

31. Oliver A. High Frequency of Hypermutable Pseudomonas aeruginosa in Cystic Fibrosis Lung Infection. Science (80-). 2000;288: 1251–1253. doi: 10.1126/science.288.5469.1251

32. Couce A, Rodríguez-Rojas A, Blázquez J. Bypass of genetic constraints during mutator evolution to antibiotic resistance. Proc Biol Sci. 2015;282: 20142698. doi: 10.1098/rspb.2014.2698 25716795

33. Imlay J a. Cellular defenses against superoxide and hydrogen peroxide. Annu Rev Biochem. 2008;77: 755–76. doi: 10.1146/annurev.biochem.77.061606.161055 18173371

34. Rodriguez-Rojas A, Couce A, Blazquez J. Frequency of spontaneous resistance to fosfomycin combined with different antibiotics in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2010/08/18 ed. 2010;54: 4948–4949. AAC.00415-10 [pii] doi: 10.1128/AAC.00415-10 20713658

35. Rodríguez-Rojas A, Maciá MD, Couce A, Gómez C, Castañeda-García A, Oliver A, et al. Assessing the Emergence of Resistance: the Absence of Biological Cost in vivo May Compromise Fosfomycin Treatments for P. aeruginosa Infections. PLoS One. 2010;(In press). doi: 10.1371/journal.pone.0010193 20419114

36. Castaneda-Garcia A, Rodriguez-Rojas A, Guelfo JR, Blazquez J. The Glycerol-3-Phosphate Permease GlpT Is the Only Fosfomycin Transporter in Pseudomonas aeruginosa. J Bacteriol. 2009/09/08 ed. 2009;191: 6968–6974. JB.00748-09 [pii] doi: 10.1128/JB.00748-09 19734311

37. Rodriguez-Rojas A, Blazquez J. The Pseudomonas aeruginosa pfpI gene plays an antimutator role and provides general stress protection. J Bacteriol. 2008/11/26 ed. 2009;191: 844–850. JB.01081-08 [pii] doi: 10.1128/JB.01081-08 19028889

38. Rodríguez-Rojas A, Maciá MD, Couce A, Gómez C, Castañeda-García A, Oliver A, et al. Assessing the emergence of resistance: the absence of biological cost in vivo may compromise fosfomycin treatments for P. aeruginosa infections. PLoS One. 2010;5: e10193. doi: 10.1371/journal.pone.0010193 20419114

39. Morgan C, Lewis PD. iMARS—Mutation analysis reporting software: An analysis of spontaneous cII mutation spectra. Mutat Res—Genet Toxicol Environ Mutagen. 2006;603: 15–26. doi: 10.1016/j.mrgentox.2005.09.010

40. McBride TJ, Preston BD, Loeb LA. Mutagenic spectrum resulting from DNA damage by oxygen radicals. Biochemistry. 1991;30: 207–13. Available: http://www.ncbi.nlm.nih.gov/pubmed/1703014 1703014

41. Juurik T, Ilves H, Teras R, Ilmjärv T, Tavita K, Ukkivi K, et al. Mutation frequency and spectrum of mutations vary at different chromosomal positions of Pseudomonas putida. PLoS One. 2012;7: e48511. doi: 10.1371/journal.pone.0048511 23119042

42. Shee C, Gibson JL, Rosenberg SM. Two mechanisms produce mutation hotspots at DNA breaks in Escherichia coli. Cell Rep. 2012;2: 714–21. doi: 10.1016/j.celrep.2012.08.033 23041320

43. Moyano AJ, Luján AM, Argaraña CE, Smania AM. MutS deficiency and activity of the error-prone DNA polymerase IV are crucial for determining mucA as the main target for mucoid conversion in Pseudomonas aeruginosa. Mol Microbiol. 2007;64: 547–59. doi: 10.1111/j.1365-2958.2007.05675.x 17493134

44. Lofton H, Pränting M, Thulin E, Andersson DI. Mechanisms and fitness costs of resistance to antimicrobial peptides LL-37, CNY100HL and wheat germ histones. PLoS One. 2013;8: e68875. doi: 10.1371/journal.pone.0068875 23894360

45. Foti JJ, Devadoss B, Winkler JA, Collins JJ, Walker GC. Oxidation of the guanine nucleotide pool underlies cell death by bactericidal antibiotics. Science. 2012;336: 315–9. doi: 10.1126/science.1219192 22517853

46. Kohanski M a, DePristo M a, Collins JJ. Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol Cell. Elsevier Ltd; 2010;37: 311–20. doi: 10.1016/j.molcel.2010.01.003 20159551

47. Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ. A common mechanism of cellular death induced by bactericidal antibiotics. Cell. 2007/09/07 ed. 2007;130: 797–810. S0092-8674(07)00899-9 [pii] doi: 10.1016/j.cell.2007.06.049 17803904

48. Dwyer DJ, Kohanski MA, Collins JJ. Role of reactive oxygen species in antibiotic action and resistance. Curr Opin Microbiol. 2009/08/04 ed. 2009;12: 482–489. S1369-5274(09)00090-3 [pii] doi: 10.1016/j.mib.2009.06.018 19647477

49. Keren I, Wu Y, Inocencio J, Mulcahy LR, Lewis K. Killing by bactericidal antibiotics does not depend on reactive oxygen species. Science. 2013;339: 1213–6. doi: 10.1126/science.1232688 23471410

50. Liu Y, mlay J a Cell Death from Antibiotics Without the Involvement of Reactive Oxygen Species. Science (80-). 2013;339: 1210–1213. doi: 10.1126/science.1232751

51. Imlay JA. Diagnosing oxidative stress in bacteria: not as easy as you might think. Curr Opin Microbiol. 2015;24C: 124–131. doi: 10.1016/j.mib.2015.01.004

52. Ward CG, Bullen JJ, Rogers HJ. Iron and infection: new developments and their implications. J Trauma. 1996/08/01 ed. 1996;41: 356–364. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8760553 8760553

53. Wessling-Resnick M. Iron homeostasis and the inflammatory response. Annu Rev Nutr. 2010;30: 105–22. doi: 10.1146/annurev.nutr.012809.104804 20420524

54. Skaar EP. The battle for iron between bacterial pathogens and their vertebrate hosts. PLoS Pathog. 2010;6: e1000949. doi: 10.1371/journal.ppat.1000949 20711357

55. Couce A, Blazquez J. Estimating mutation rates in low-replication experiments. Mutat Res. 2011/07/09 ed. 2011;In Press. S0027-5107(11)00147-3 [pii] doi: 10.1016/j.mrfmmm.2011.06.005 21736881

56. Hall BM, Ma C- X, Liang P, Singh KK. Fluctuation analysis CalculatOR: a web tool for the determination of mutation rate using Luria-Delbruck fluctuation analysis. Bioinformatics. 2009;25: 1564–5. doi: 10.1093/bioinformatics/btp253 19369502

57. West SE, Schweizer HP, Dall C, Sample AK, Runyen-Janecky LJ. Construction of improved Escherichia-Pseudomonas shuttle vectors derived from pUC18/19 and sequence of the region required for their replication in Pseudomonas aeruginosa. Gene. 1994/10/11 ed. 1994;148: 81–86. 0378-1119(94)90237-2 [pii] 7926843

58. Vilchèze C, Hartman T, Weinrick B, Jacobs WR. Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction. Nat Commun. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.; 2013;4: 1881. doi: 10.1038/ncomms2898 23695675

59. Riemer J, Hoepken HH, Czerwinska H, Robinson SR, Dringen R. Colorimetric ferrozine-based assay for the quantitation of iron in cultured cells. Anal Biochem. 2004;331: 370–5. doi: 10.1016/j.ab.2004.03.049 15265744