Antibiotic Modulation of Capsular Exopolysaccharide and Virulence in

English version České info

Acinetobacter baumannii has gained notoriety as a cause of hospital-acquired infections that are difficult to treat due to extensive antibiotic resistance. While the microorganism rarely causes disease in the community, it commonly infects patients receiving antibiotics. The factors intrinsic to the bacterium that enable growth in the presence of antibiotics are not well characterized. Furthermore, the consequences of subinhibitory antibiotic concentrations on A. baumannii disease are unknown. Here we examined the K locus, a bacterial disease determinant responsible for the production of protective surface polysaccharides, and asked whether this determinant also contributes to antibiotic resistance. We found that K locus polysaccharides facilitate resistance to multiple antibiotics, and, unexpectedly, that the bacterium responds to certain antibiotics at subinhibitory concentrations by increasing production of capsule, the principal K locus polysaccharide. This augmented production of capsule, which is mediated by upregulation of K locus gene expression, increased the ability of the bacterium to overcome attack by the complement system, an important anti-pathogen host defense, and result in lethal disease during experimental bloodstream infection in mice. Our studies indicate that A. baumannii increases its disease-causing potential in the setting of inadequate antibiotic treatment, which may promote the development of opportunistic infections.

Vyšlo v časopise: Antibiotic Modulation of Capsular Exopolysaccharide and Virulence in. PLoS Pathog 11(2): e32767. doi:10.1371/journal.ppat.1004691
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004691

Souhrn

Zdroje

1. Peleg AY, Seifert H, Paterson DL (2008) Acinetobacter baumannii: emergence of a successful pathogen. Clin Microbiol Rev 21: 538–582. doi: 10.1128/CMR.00058-07 18625687

2. Chitnis AS, Edwards JR, Ricks PM, Sievert DM, Fridkin SK, et al. (2012) Device-associated infection rates, device utilization, and antimicrobial resistance in long-term acute care hospitals reporting to the National Healthcare Safety Network, 2010. Infect Control Hosp Epidemiol 33: 993–1000. doi: 10.1086/667745 22961018

3. Hidron AI, Edwards JR, Patel J, Horan TC, Sievert DM, et al. (2008) NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006–2007. Infect Control Hosp Epidemiol 29: 996–1011. doi: 10.1086/591861 18947320

4. Lockhart SR, Abramson MA, Beekmann SE, Gallagher G, Riedel S, et al. (2007) Antimicrobial resistance among Gram-negative bacilli causing infections in intensive care unit patients in the United States between 1993 and 2004. J Clin Microbiol 45: 3352–3359. 17715376

5. Sievert DM, Ricks P, Edwards JR, Schneider A, Patel J, et al. (2013) Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009–2010. Infect Control Hosp Epidemiol 34: 1–14. doi: 10.1086/668770 23221186

6. Doi Y, Husain S, Potoski BA, McCurry KR, Paterson DL (2009) Extensively drug-resistant Acinetobacter baumannii. Emerg Infect Dis 15: 980–982. doi: 10.3201/eid1506.081006 19523312

7. Park YK, Peck KR, Cheong HS, Chung DR, Song JH, et al. (2009) Extreme drug resistance in Acinetobacter baumannii infections in intensive care units, South Korea. Emerg Infect Dis 15: 1325–1327. 19751609

8. Valencia R, Arroyo LA, Conde M, Aldana JM, Torres MJ, et al. (2009) Nosocomial outbreak of infection with pan-drug-resistant Acinetobacter baumannii in a tertiary care university hospital. Infect Control Hosp Epidemiol 30: 257–263. doi: 10.1086/595977 19199531

9. Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, et al. (2009) Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 48: 1–12. doi: 10.1086/595011 19035777

10. Food and Drug Administration H (2013) Establishing a List of Qualifying Pathogens Under the Food and Drug Administration Safety and Innovation Act. Federal Register. pp. 35155–35173.

11. Feldman C, Kassel M, Cantrell J, Kaka S, Morar R, et al. (1999) The presence and sequence of endotracheal tube colonization in patients undergoing mechanical ventilation. Eur Respir J 13: 546–551. 10232424

12. Gil-Perotin S, Ramirez P, Marti V, Sahuquillo JM, Gonzalez E, et al. (2012) Implications of endotracheal tube biofilm in ventilator-associated pneumonia response: a state of concept. Crit Care 16: R93. doi: 10.1186/cc11357 22621676

13. Anstey NM, Currie BJ, Withnall KM (1992) Community-acquired Acinetobacter pneumonia in the Northern Territory of Australia. Clin Infect Dis 14: 83–91. 1571467

14. Garnacho-Montero J, Ortiz-Leyba C, Fernandez-Hinojosa E, Aldabo-Pallas T, Cayuela A, et al. (2005) Acinetobacter baumannii ventilator-associated pneumonia: epidemiological and clinical findings. Intensive Care Med 31: 649–655. 15785929

15. Joung MK, Kwon KT, Kang CI, Cheong HS, Rhee JY, et al. (2010) Impact of inappropriate antimicrobial therapy on outcome in patients with hospital-acquired pneumonia caused by Acinetobacter baumannii. J Infect 61: 212–218. doi: 10.1016/j.jinf.2010.06.014 20600295

16. Hood MI, Becker KW, Roux CM, Dunman PM, Skaar EP (2013) genetic determinants of intrinsic colistin tolerance in Acinetobacter baumannii. Infect Immun 81: 542–551. doi: 10.1128/IAI.00704-12 23230287

17. Lees-Miller RG, Iwashkiw JA, Scott NE, Seper A, Vinogradov E, et al. (2013) A common pathway for O-linked protein-glycosylation and synthesis of capsule in Acinetobacter baumannii. Mol Microbiol 89: 816–830. doi: 10.1111/mmi.12300 23782391

18. Lin L, Tan B, Pantapalangkoor P, Ho T, Baquir B, et al. (2012) Inhibition of LpxC protects mice from resistant Acinetobacter baumannii by modulating inflammation and enhancing phagocytosis. MBio 3. doi: 10.1128/mBio.00535-12 23269830

19. Luke NR, Sauberan SL, Russo TA, Beanan JM, Olson R, et al. (2010) Identification and characterization of a glycosyltransferase involved in Acinetobacter baumannii lipopolysaccharide core biosynthesis. Infect Immun 78: 2017–2023. doi: 10.1128/IAI.00016-10 20194587

20. Russo TA, Luke NR, Beanan JM, Olson R, Sauberan SL, et al. (2010) The K1 capsular polysaccharide of Acinetobacter baumannii strain 307–0294 is a major virulence factor. Infect Immun 78: 3993–4000. doi: 10.1128/IAI.00366-10 20643860

21. Russo TA, MacDonald U, Beanan JM, Olson R, MacDonald IJ, et al. (2009) Penicillin-binding protein 7/8 contributes to the survival of Acinetobacter baumannii in vitro and in vivo. J Infect Dis 199: 513–521. doi: 10.1086/596317 19143563

22. Umland TC, Schultz LW, MacDonald U, Beanan JM, Olson R, et al. (2012) In vivo-validated essential genes identified in Acinetobacter baumannii by using human ascites overlap poorly with essential genes detected on laboratory media. MBio 3. doi: 10.1128/mBio.00499-12 23249812

23. Koeleman JG, van der Bijl MW, Stoof J, Vandenbroucke-Grauls CM, Savelkoul PH (2001) Antibiotic resistance is a major risk factor for epidemic behavior of Acinetobacter baumannii. Infect Control Hosp Epidemiol 22: 284–288. 11428438

24. Hu D, Liu B, Dijkshoorn L, Wang L, Reeves PR (2013) Diversity in the major polysaccharide antigen of Acinetobacter baumannii assessed by DNA sequencing, and development of a molecular serotyping scheme. PLoS One 8: e70329. doi: 10.1371/journal.pone.0070329 23922982

25. Kenyon JJ, Hall RM (2013) Variation in the complex carbohydrate biosynthesis loci of Acinetobacter baumannii genomes. PLoS One 8: e62160. doi: 10.1371/journal.pone.0062160 23614028

26. Russo TA, Beanan JM, Olson R, MacDonald U, Cox AD, et al. (2013) The K1 capsular polysaccharide from Acinetobacter baumannii is a potential therapeutic target via passive immunization. Infect Immun 81: 915–922. doi: 10.1128/IAI.01184-12 23297385

27. Nikaido H (2003) Molecular basis of bacterial outer membrane permeability revisited. Microbiol Mol Biol Rev 67: 593–656. 14665678

28. Sugawara E, Nikaido H (2012) OmpA is the principal nonspecific slow porin of Acinetobacter baumannii. J Bacteriol 194: 4089–4096. doi: 10.1128/JB.00435-12 22636785

29. Coyne S, Courvalin P, Perichon B (2011) Efflux-mediated antibiotic resistance in Acinetobacter spp. Antimicrob Agents Chemother 55: 947–953. doi: 10.1128/AAC.01388-10 21173183

30. Campos MA, Vargas MA, Regueiro V, Llompart CM, Alberti S, et al. (2004) Capsule polysaccharide mediates bacterial resistance to antimicrobial peptides. Infect Immun 72: 7107–7114. 15557634

31. Spinosa MR, Progida C, Tala A, Cogli L, Alifano P, et al. (2007) The Neisseria meningitidis capsule is important for intracellular survival in human cells. Infect Immun 75: 3594–3603. 17470547

32. Zaragoza O, Chrisman CJ, Castelli MV, Frases S, Cuenca-Estrella M, et al. (2008) Capsule enlargement in Cryptococcus neoformans confers resistance to oxidative stress suggesting a mechanism for intracellular survival. Cell Microbiol 10: 2043–2057. doi: 10.1111/j.1462-5822.2008.01186.x 18554313

33. Llobet E, Tomas JM, Bengoechea JA (2008) Capsule polysaccharide is a bacterial decoy for antimicrobial peptides. Microbiology 154: 3877–3886. doi: 10.1099/mic.0.2008/022301-0 19047754

34. Jones A, Georg M, Maudsdotter L, Jonsson AB (2009) Endotoxin, capsule, and bacterial attachment contribute to Neisseria meningitidis resistance to the human antimicrobial peptide LL-37. J Bacteriol 191: 3861–3868. doi: 10.1128/JB.01313-08 19376861

35. Cole JN, Pence MA, von Kockritz-Blickwede M, Hollands A, Gallo RL, et al. (2010) M protein and hyaluronic acid capsule are essential for in vivo selection of covRS mutations characteristic of invasive serotype M1T1 group A Streptococcus. MBio 1. doi: 10.1128/mBio.00307-10 21179522

36. Whitfield C (2006) Biosynthesis and assembly of capsular polysaccharides in Escherichia coli. Annu Rev Biochem 75: 39–68. 16756484

37. Grangeasse C, Cozzone AJ, Deutscher J, Mijakovic I (2007) Tyrosine phosphorylation: an emerging regulatory device of bacterial physiology. Trends Biochem Sci 32: 86–94. 17208443

38. Yother J (2011) Capsules of Streptococcus pneumoniae and other bacteria: paradigms for polysaccharide biosynthesis and regulation. Annu Rev Microbiol 65: 563–581. doi: 10.1146/annurev.micro.62.081307.162944 21721938

39. Karlyshev AV, Wren BW (2001) Detection and initial characterization of novel capsular polysaccharide among diverse Campylobacter jejuni strains using alcian blue dye. J Clin Microbiol 39: 279–284. 11136784

40. Mercaldi MP, Dams-Kozlowska H, Panilaitis B, Joyce AP, Kaplan DL (2008) Discovery of the dual polysaccharide composition of emulsan and the isolation of the emulsion stabilizing component. Biomacromolecules 9: 1988–1996. doi: 10.1021/bm800239p 18547107

41. Fregolino E, Gargiulo V, Lanzetta R, Parrilli M, Holst O, et al. (2011) Identification and structural determination of the capsular polysaccharides from two Acinetobacter baumannii clinical isolates, MG1 and SMAL. Carbohydr Res 346: 973–977. doi: 10.1016/j.carres.2011.03.024 21463855

42. Iwashkiw JA, Seper A, Weber BS, Scott NE, Vinogradov E, et al. (2012) Identification of a general O-linked protein glycosylation system in Acinetobacter baumannii and its role in virulence and biofilm formation. PLoS Pathog 8: e1002758. doi: 10.1371/journal.ppat.1002758 22685409

43. Choi AH, Slamti L, Avci FY, Pier GB, Maira-Litran T (2009) The pgaABCD locus of Acinetobacter baumannii encodes the production of poly-beta-1–6-N-acetylglucosamine, which is critical for biofilm formation. J Bacteriol 191: 5953–5963. doi: 10.1128/JB.00647-09 19633088

44. Roantree RJ, Kuo TT, MacPhee DG (1977) The effect of defined lipopolysaccharide core defects upon antibiotic resistances of Salmonella typhimurium. J Gen Microbiol 103: 223–234. 340606

45. Jeon B, Muraoka W, Scupham A, Zhang Q (2009) Roles of lipooligosaccharide and capsular polysaccharide in antimicrobial resistance and natural transformation of Campylobacter jejuni. J Antimicrob Chemother 63: 462–468. doi: 10.1093/jac/dkn529 19147521

46. Nikaido H, Vaara M (1985) Molecular basis of bacterial outer membrane permeability. Microbiol Rev 49: 1–32. 2580220

47. Morita Y, Tomida J, Kawamura Y (2014) Responses of to antimicrobials. Front Microbiol 4: 422. doi: 10.3389/fmicb.2013.00422 24409175

48. Breslow JM, Meissler JJ Jr, Hartzell RR, Spence PB, Truant A, et al. (2011) Innate immune responses to systemic Acinetobacter baumannii infection in mice: neutrophils, but not interleukin-17, mediate host resistance. Infect Immun 79: 3317–3327. doi: 10.1128/IAI.00069-11 21576323

49. Bruhn KW, Pantapalangkoor P, Nielsen T, Tan B, Junus J, et al. (2014) Host Fate is Rapidly Determined by Innate Effector-Microbial Interactions During Acinetobacter baumannii Bacteremia. J Infect Dis. 25552371

50. Hood MI, Mortensen BL, Moore JL, Zhang Y, Kehl-Fie TE, et al. (2012) Identification of an Acinetobacter baumannii zinc acquisition system that facilitates resistance to calprotectin-mediated zinc sequestration. PLoS Pathog 8: e1003068. doi: 10.1371/journal.ppat.1003068 23236280

51. Jiang W, Jones P, Inouye M (1993) Chloramphenicol induces the transcription of the major cold shock gene of Escherichia coli, cspA. J Bacteriol 175: 5824–5828. 8376329

52. Lelivelt MJ, Kawula TH (1995) Hsc66, an Hsp70 homolog in Escherichia coli, is induced by cold shock but not by heat shock. J Bacteriol 177: 4900–4907. 7665466

53. VanBogelen RA, Neidhardt FC (1990) Ribosomes as sensors of heat and cold shock in Escherichia coli. Proc Natl Acad Sci U S A 87: 5589–5593. 2198567

54. Inouye M, Phadtare S (2004) Cold shock response and adaptation at near-freezing temperature in microorganisms. Sci STKE 2004: pe26.

55. Phadtare S, Severinov K (2010) RNA remodeling and gene regulation by cold shock proteins. RNA Biol 7: 788–795. 21045540

56. Tomaras AP, Flagler MJ, Dorsey CW, Gaddy JA, Actis LA (2008) Characterization of a two-component regulatory system from Acinetobacter baumannii that controls biofilm formation and cellular morphology. Microbiology 154: 3398–3409. doi: 10.1099/mic.0.2008/019471-0 18957593

57. Liou ML, Soo PC, Ling SR, Kuo HY, Tang CY, et al. (2013) The sensor kinase BfmS mediates virulence in Acinetobacter baumannii. J Microbiol Immunol Infect. doi: 10.1016/j.jmii.2013.09.010 24388586

58. Wang N, Ozer EA, Mandel MJ, Hauser AR (2014) Genome-wide identification of Acinetobacter baumannii genes necessary for persistence in the lung. MBio 5: e01163–01114. doi: 10.1128/mBio.01163-14 24895306

59. Capra EJ, Perchuk BS, Lubin EA, Ashenberg O, Skerker JM, et al. (2010) Systematic dissection and trajectory-scanning mutagenesis of the molecular interface that ensures specificity of two-component signaling pathways. PLoS Genet 6: e1001220. doi: 10.1371/journal.pgen.1001220 21124821

60. Davies J, Spiegelman GB, Yim G (2006) The world of subinhibitory antibiotic concentrations. Curr Opin Microbiol 9: 445–453. 16942902

61. Rubinovitz C, Gutnick DL, Rosenberg E (1982) Emulsan production by Acinetobacter calcoaceticus in the presence of chloramphenicol. J Bacteriol 152: 126–132. 6896872

62. Nakar D, Gutnick DL (2001) Analysis of the wee gene cluster responsible for the biosynthesis of the polymeric bioemulsifier from the oil-degrading strain Acinetobacter lwoffii RAG-1. Microbiology 147: 1937–1946. 11429470

63. Boehm A, Steiner S, Zaehringer F, Casanova A, Hamburger F, et al. (2009) Second messenger signalling governs Escherichia coli biofilm induction upon ribosomal stress. Mol Microbiol 72: 1500–1516. doi: 10.1111/j.1365-2958.2009.06739.x 19460094

64. Hoffman LR, D’Argenio DA, MacCoss MJ, Zhang Z, Jones RA, et al. (2005) Aminoglycoside antibiotics induce bacterial biofilm formation. Nature 436: 1171–1175. 16121184

65. Elliott D, Burns JL, Hoffman LR (2010) Exploratory study of the prevalence and clinical significance of tobramycin-mediated biofilm induction in Pseudomonas aeruginosa isolates from cystic fibrosis patients. Antimicrob Agents Chemother 54: 3024–3026. doi: 10.1128/AAC.00102-10 20404125

66. Ichimiya T, Takeoka K, Hiramatsu K, Hirai K, Yamasaki T, et al. (1996) The influence of azithromycin on the biofilm formation of Pseudomonas aeruginosa in vitro. Chemotherapy 42: 186–191. 8983885

67. Held TK, Adamczik C, Trautmann M, Cross AS (1995) Effects of MICs and sub-MICs of antibiotics on production of capsular polysaccharide of Klebsiella pneumoniae. Antimicrob Agents Chemother 39: 1093–1096. 7625794

68. Kristian SA, Timmer AM, Liu GY, Lauth X, Sal-Man N, et al. (2007) Impairment of innate immune killing mechanisms by bacteriostatic antibiotics. FASEB J 21: 1107–1116. 17215486

69. Luong TT, Lee CY (2002) Overproduction of type 8 capsular polysaccharide augments Staphylococcus aureus virulence. Infect Immun 70: 3389–3395. 12065477

70. Miskinyte M, Sousa A, Ramiro RS, de Sousa JA, Kotlinowski J, et al. (2013) The genetic basis of Escherichia coli pathoadaptation to macrophages. PLoS Pathog 9: e1003802. doi: 10.1371/journal.ppat.1003802 24348252

71. Thakker M, Park JS, Carey V, Lee JC (1998) Staphylococcus aureus serotype 5 capsular polysaccharide is antiphagocytic and enhances bacterial virulence in a murine bacteremia model. Infect Immun 66: 5183–5189. 9784520

72. Ophir T, Gutnick DL (1994) A role for exopolysaccharides in the protection of microorganisms from desiccation. Appl Environ Microbiol 60: 740–745. 16349202

73. Govan JR (1975) Mucoid strains of Pseudomonas aeruginosa: the influence of culture medium on the stability of mucus production. J Med Microbiol 8: 513–522. 812998

74. Rajagopal S, Sudarsan N, Nickerson KW (2002) Sodium dodecyl sulfate hypersensitivity of clpP and clpB mutants of Escherichia coli. Appl Environ Microbiol 68: 4117–4121. 12147516

75. Cosgrove SAE (2013) Antibiotic Guidelines 2013–2014: Treatment Recommendations For Adult Inpatients. The Johns Hopkins Hospital Antimicrobial Stewardship Program.

76. Traub WH, Bauer D (2000) Surveillance of nosocomial cross-infections due to three Acinetobacter genospecies (Acinetobacter baumannii, genospecies 3 and genospecies 13) during a 10-Year Observation period: serotyping, macrorestriction analysis of Genomic DNA and antibiotic susceptibilities. Chemotherapy 46: 282–292. 10859434

77. Choi KH, Kumar A, Schweizer HP (2006) A 10-min method for preparation of highly electrocompetent Pseudomonas aeruginosa cells: application for DNA fragment transfer between chromosomes and plasmid transformation. J Microbiol Methods 64: 391–397. 15987659

78. Kumar A, Dalton C, Cortez-Cordova J, Schweizer HP (2010) Mini-Tn7 vectors as genetic tools for single copy gene cloning in Acinetobacter baumannii. J Microbiol Methods 82: 296–300. doi: 10.1016/j.mimet.2010.07.002 20638421

79. Choi KH, Mima T, Casart Y, Rholl D, Kumar A, et al. (2008) Genetic tools for select-agent-compliant manipulation of Burkholderia pseudomallei. Appl Environ Microbiol 74: 1064–1075. 18156318

80. Vogel HJ, Bonner DM (1956) Acetylornithinase of Escherichia coli: partial purification and some properties. J Biol Chem 218: 97–106. 13278318

81. Ensminger AW, Yassin Y, Miron A, Isberg RR (2012) Experimental evolution of Legionella pneumophila in mouse macrophages leads to strains with altered determinants of environmental survival. PLoS Pathog 8: e1002731. doi: 10.1371/journal.ppat.1002731 22693450

82. Duguid JP (1951) The demonstration of bacterial capsules and slime. J Pathol Bacteriol 63: 673–685. 14898372

83. Hitchcock PJ, Brown TM (1983) Morphological heterogeneity among Salmonella lipopolysaccharide chemotypes in silver-stained polyacrylamide gels. J Bacteriol 154: 269–277. 6187729

84. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402–408. 11846609

85. Gao R, Stock AM (2009) Biological insights from structures of two-component proteins. Annu Rev Microbiol 63: 133–154. doi: 10.1146/annurev.micro.091208.073214 19575571