Acinetobacter baumannii: Resistance and Virulence mediated through bacterial type IV secretion system
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Introduction: Type IV Bacterial Secretion Systems (TFSS) have a variety of biological functions such as the exchange of genetic material with other bacteria and virulent translocation of DNA with its effector proteins into host cells. A. baumannii is a pathogen that causes infections in humans and exhibits high rates of multidrug resistance to drugs.
Objective: To relate how type IV secretion systems is associated with patterns of resistance and virulence in A. baumannii.
Materials and Methods: Exhaustive search in PMC (NCBI) using a set of keywords was performed. Results: The search yielded 133 articles. Fourteen articles were analysed to determine the bacterial secretion system and the resistant and virulence of AA. baumannii.
Conclusions: Systems of bacterial type IV secretion present in A. baumannii are crucial in understanding the patterns of virulence and resistance.
Key words: Pathogenicity, type four secretion system (T4SS), A. baumannii, virulence factors, multidrug bacterial resistance (MDR), horizontal gene transfer (HGT).
Zúñiga-Bahamon, A., Tobar, F., Duque, J. F., & Moreno, P. (2013). Acinetobacter baumannii: Resistance and Virulence mediated through bacterial type IV secretion system. Revista Estomatología, 21(2), 37–45. https://doi.org/10.25100/re.v21i2.5765
1. Sader HS, Jones RN, Gales AC, Silva JB, Pignatari AC. SENTRY antimicrobial surveillance program report: Latin American and Brazilian results for 1997 through 2001. The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases. 2004; 8(1):25-79.
2. Poole K. Resistance to beta-lactam antibiotics. Cellular and molecular life sciences : CMLS. 2004; 61(17):2200-23.
3. Cabrera CE, Gómez RF, Zúñiga AE. Resistance to bacterial antibiotics, antiseptics and disinfectants a manifestation of the survival and adaptation mechanisms. Colombia Médica. 2007; 38(2):149-58.
4. Villegas MV, Kattan JN, Correa A, Lolans K, Guzman AM, Woodford N, et al. Dissemination of Acinetobacter
baumannii clones with OXA-23 Carbapenemase in Colombian hospitals. Antimicrobial Agents and Chemotherapy. 2007; 51(6):2001-4.
5. Dobrindt U, Hochhut B, Hentschel U, Hacker J. Genomic islands in pathogenic and environmental microorganisms. Nature reviews Microbiology. 2004; 2(5):414-24. P
6. Thanassi DG, Hultgren SJ. Multiple pathways allow protein secretion across the bacterial outer membrane. Current opinion in cell biology. 2000; 12(4):420- 30.
7. Llosa M, Schroder G, Dehio C. New perspectives into bacterial DNA transfer to human cells. Trends in Microbiology. 2012; 20(8):355-9.
8. Averhoff B. DNA transport and natural transformation in mesophilic and thermophilic bacteria. Journal of
bioenergetics and biomembranes. 2004; 36(1):25-33.
9. Averhoff B, Friedrich A. Type IV pili-related natural transformation systems: DNA transport in mesophilic
and thermophilic bacteria. Archives of microbiology. 2003; 180(6):385-93.
10. Dorsey CW, Tomaras AP, Connerly PL, Tolmasky ME, Crosa JH, Actis LA. The siderophore-mediated iron
acquisition systems of Acinetobacter baumannii ATCC 19606 and Vibrio anguillarum 775 are structurally and functionally related. Microbiology. 2004; 150(Pt 11):3657-67.
11. Tomaras AP, Dorsey CW, Edelmann RE, Actis LA. Attachment to and biofilm formation on abiotic surfaces by Acinetobacter baumannii: involvement of a novel chaperone-usher pili assembly system. Microbiology. 2003; 149(Pt 12):3473-84.
12. Choi CH, Lee EY, Lee YC, Park TI, Kim HJ, Hyun SH, et al. Outer membrane protein 38 of Acinetobacter baumannii localizes to the mitochondria and induces apoptosis of epithelial cells. Cellular microbiology. 2005; 7(8):1127-38.
13. Vasil ML, Tomaras AP, Pritchard AE. Identification and Evaluation of Twin-Arginine Translocase Inhibitors. Antimicrobial Agents and Chemotherapy. 2012; 56(12):6223-34.
14. Echenique JR, Arienti H, Tolmasky ME, Read RR, Staneloni RJ, Crosa JH, et al. Characterization of a high-affinity iron transport system in Acinetobacter baumannii. Journal of Bacteriology. 1992; 174(23):7670-9.
15. Sahu PK, Iyer PS, Gaikwad MB, Talreja SC, Pardesi KR, Chopade BA. An MFS Transporter-Like ORF from MDR Acinetobacter baumannii AIIMS 7 IsAssociated with Adherence and Biofilm Formation on Biotic/Abiotic Surface. International Journal of Microbiology. 2012.
16. Vallenet D, Nordmann P, Barbe V, Poirel L, Mangenot S, Bataille E, et al. Comparative Analysis of Acinetobacters: Three Genomes for Three Lifestyles. PLoS ONE. 2008; 3(3). P
17. Weber BS, Miyata ST, Iwashkiw JA, Mortensen BL, Skaar EP, Pukatzki S, et al. Genomic and Functional Analysis of the Type VI Secretion System in Acinetobacter. PLoS One. 2013; 8(1):e55142.
18. Harding CM, Tracy EN, Carruthers MD, Rather PN, Actis LA, Munson RS. Acinetobacter baumannii Strain M2 Produces Type IV Pili Which Play a Role in Natural Transformation and Twitching Motility but Not Surface-Associated Motility. mBio. 2013; 4(4).
19. Smith MG, Gianoulis TA, Pukatzki S, Mekalanos JJ, Ornston LN, Gerstein M, et al. New insights into Acinetobacter baumannii pathogenesis revealed by highdensity pyrosequencing and transposon mutagenesis. Genes & Development. 2007; 21(5):601-14.
20. Sahl JW, Johnson JK, Harris AD, Phillippy AM, Hsiao WW, Thom KA, et al. Genomic comparison of multi-drug resistant invasive and colonizing Acinetobacter baumannii isolated from diverse human body sites reveals genomic plasticity. BMC Genomics. 2011;12:291.
21. Henry R, Vithanage N, Harrison P, Seemann T, Coutts S, Moffatt JH, et al. Colistin-Resistant, Lipopolysaccharide- Deficient Acinetobacter baumannii Responds to Lipopolysaccharide Loss through Increased Expression of Genes Involved in the Synthesis and Transport of Lipoproteins, Phospholipids, and
Poly-?- 1,6-N-Acetylglucosamine. Antimicrobial Agents and Chemotherapy. 2012;
56(1):59-69.
22. Marti S, Nait Chabane Y, Alexandre S, Coquet L, Vila J, Jouenne T, et al. Growth of Acinetobacter baumannii in Pellicle Enhanced the Expression of Potential Virulence Factors. PLoS ONE. 2011;6(10).
23. Zhu L, Yan Z, Zhang Z, Zhou Q, Zhou J, Wakeland EK, et al. Complete Genome Analysis of Three Acinetobacter baumannii Clinical Isolates in China for Insight into the Diversification of Drug Resistance Elements. PLoS ONE. 2013; 8(6).
24. Miranda MC, Perez F, Zuluaga T, et al. Antimicrobial resistance in gram negative bacteria isolated from intensive care units of Colombian hospitals, WHONET 2003, 2004 and 2005. Biomedica 2006; 26(3):424-33.
25. Groisman EA, Ochman H. Pathogenicity islands: bacterial evolution in quantum leaps. Cell. 1996; 87(5):791-4.
26. Dijkshoorn L, Nemec A, Seifert H. An increasing threat in hospitals: multidrugresistant Acinetobacter baumannii. Nature reviews Microbiology. 2007; 5(12):939- 51.
27. Schmidt H, Hensel M. Pathogenicity Islands in Bacterial Pathogenesis. Clinical Microbiology Reviews. 2004; 17(1):14- 56.
28. Backert S, Meyer TF. Type IV secretion systems and their effectors in bacterial pathogenesis. Current opinion in microbiology. 2006; 9(2):207-17.
29. Gohl O, Friedrich A, Hoppert M, Averhoff B. The thin pili of Acinetobacter sp. strain BD413 mediate adhesion to biotic and abiotic surfaces. Applied and Environmental Microbiology. 2006; 72(2):1394-401.
30. Fournier PE, Vallenet D, Barbe V, Audic S, Ogata H, Poirel L, et al. Comparative genomics of multidrug resistance in Acinetobacter baumannii. PLoS Genetics. 2006; 2(1):e7.
31. Segal G, Feldman M, Zusman T. The Icm/Dot type-IV secretion systems of Legionella pneumophila and Coxiella burnetii. FEMS microbiology reviews. 2005; 29(1):65-81.
32. Vogel JP, Andrews HL, Wong SK, Isberg RR. Conjugative Transfer by the Virulence System of Legionella pneumophila. Science. 1998; 279(5352):873-6.
33. Vincent CD, Friedman JR, Jeong KC, Buford EC, Miller JL, Vogel JP. Identification of the core transmembrane complex of the Legionella Dot/Icm type IV secretion system. Molecular Microbiology. 2006; 62(5):1278-91.
34. Ou HY, Chen LL, Lonnen J, Chaudhuri RR, Thani AB, Smith R, et al. A novel strategy for the identification of
genomic islands by comparative analysis of the contents and contexts of tRNA sites in closely related bacteria. Nucleic Acids Research. 2006; 34(1):e3.
35. Hacker J, Carniel E. Ecological fitness, genomic islands and bacterial pathogenicity. A Darwinian view of the evolution of microbes. EMBO reports. 2001; 2(5):376-81.
36. Mantri Y, Williams KP. Islander: a database of integrative islands in prokaryotic genomes, the associated integrases and their DNA site specificities. Nucleic Acids Research. 2004; 32(Database issue):D55-8.
37. Hsiao W, Wan I, Jones SJ, Brinkman FS. IslandPath: aiding detection of genomic islands in prokaryotes. Bioinformatics. 2003;19(3):418-20.
38. Grohmann E, Muth G, Espinosa M. Conjugative plasmid transfer in grampositive bacteria. Microbiology and Molecular Biology Reviews: MMBR. 2003; 67(2):277-301
39. Schroder G, Lanka E. The mating pair formation system of conjugative plasmids-A versatile secretion machinery for transfer of proteins and DNA. Plasmid. 2005; 54(1):1-25.
40. Cascales E, Christie PJ. The versatile bacterial type IV secretion systems. Nature reviews Microbiology. 2003; 1(2):137-49.
41. Sexton JA, Vogel JP. Type IVB secretion by intracellular pathogens. Traffic (Copenhagen, Denmark). 2002; 3(3):178- 85.
42. Karnholz A, Hoefler C, Odenbreit S, Fischer W, Hofreuter D, Haas R. Functional and topological characterization of novel components of the comB DNA transformation competence system in Helicobacter pylori. Journal of Bacteriology. 2006; 188(3):882-93.
43. Backert S, Kwok T, Konig W. Conjugative plasmid DNA transfer in Helicobacter pylori mediated by chromosomallyencoded relaxase and TraG-like proteins. Microbiology. 2005; 151(Pt 11):3493-503.
44. Miyamoto H, Yoshida S, Taniguchi H, Shuman HA. Virulence conversion of Legionella pneumophila by conjugal transfer of chromosomal DNA. Journal of Bacteriology. 2003; 185(22):6712-8.
45. Dorsey CW, Beglin MS, Actis LA. Detection and analysis of iron uptake components expressed by Acinetobacter baumannii clinical isolates. Journal of clinical microbiology. 2003; 41(9):4188- 93.
46. Bassili A, Fitzpatrick C, Qadeer E, Fatima R, Floyd K, Jaramillo E. A systematic review of the effectiveness of hospitaland ambulatory-based management of multidrug-resistant tuberculosis. The American journal of tropical medicine and hygiene. 2013; 89(2):271-80.
47. Sommer R, Joachim I, Wagner S, Titz A. New approaches to control infections: antibiofilm strategies against gram-negative bacteria. Chimia. 2013; 67(4):286-90.
48. Jaramillo EL. Resistencia bacteriana a los antibióticos en la Unidad de Cuidados Intensivos, Hospital de Caldas, 1992- 1994. Colombia Médica. 1996; 27(2):69- 76.
49. Pa ine K, Flowe r DR. Ba c t e r i a l bioinformatics: pathogenesis and the genome. Journal of molecular
microbiology and biotechnology. 2002; 4(4):357-65.
50. Haley RW. Measuring the costs of nosocomial infections: Methods for estimating economic burden on the
hospital. The American Journal of Medicine. 1991; 91(suppl 2):S32-S8.
51. Grant JR, Stothard P. The CGView Server: a comparative genomics tool for circular genomes. Nucleic Acids Research. 2008; 36(suppl 2):W181-W4.
52. Karlin S. Detecting anomalous gene clusters and pathogenicity islands in diverse bacterial genomes. Trends in Microbiology. 2001; 9(7):335-43.
53. Tu Q, Ding D. Detecting pathogenicity islands and anomalous gene clusters by iterative discriminant analysis. FEMS microbiology letters. 2003; 221(2):269-75.
54. Abbott JC, Aanensen DM, Rutherford K, Butcher S, Spratt BG. WebACT-an online companion for the Artemis Comparison Tool. Bioinformatics. 2005; 21(18):3665- 6.
55. Carver TJ, Rutherford KM, Berriman M, Rajandream MA, Barrell BG, Parkhill J. ACT: the Artemis Comparison Tool. Bioinformatics. 2005; 21(16):3422-3.
56. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. Journal of molecular biology. 1990; 215(3):403-10.
57. Saenz HL, Engel P, Stoeckli MC, Lanz C, Raddatz G, Vayssier-Taussat M, et al. Genomic analysis of Bartonella identifies type IV secretion systems as host adaptability factors. Nature genetics. 2007;39(12):1469-
76.
58. Rutherford K, Parkhill J, Crook J, Horsnell T, Rice P, Rajandream MA, et al. Artemis: sequence visualization and annotation. Bioinformatics. 2000; 16(10):944-5.
2. Poole K. Resistance to beta-lactam antibiotics. Cellular and molecular life sciences : CMLS. 2004; 61(17):2200-23.
3. Cabrera CE, Gómez RF, Zúñiga AE. Resistance to bacterial antibiotics, antiseptics and disinfectants a manifestation of the survival and adaptation mechanisms. Colombia Médica. 2007; 38(2):149-58.
4. Villegas MV, Kattan JN, Correa A, Lolans K, Guzman AM, Woodford N, et al. Dissemination of Acinetobacter
baumannii clones with OXA-23 Carbapenemase in Colombian hospitals. Antimicrobial Agents and Chemotherapy. 2007; 51(6):2001-4.
5. Dobrindt U, Hochhut B, Hentschel U, Hacker J. Genomic islands in pathogenic and environmental microorganisms. Nature reviews Microbiology. 2004; 2(5):414-24. P
6. Thanassi DG, Hultgren SJ. Multiple pathways allow protein secretion across the bacterial outer membrane. Current opinion in cell biology. 2000; 12(4):420- 30.
7. Llosa M, Schroder G, Dehio C. New perspectives into bacterial DNA transfer to human cells. Trends in Microbiology. 2012; 20(8):355-9.
8. Averhoff B. DNA transport and natural transformation in mesophilic and thermophilic bacteria. Journal of
bioenergetics and biomembranes. 2004; 36(1):25-33.
9. Averhoff B, Friedrich A. Type IV pili-related natural transformation systems: DNA transport in mesophilic
and thermophilic bacteria. Archives of microbiology. 2003; 180(6):385-93.
10. Dorsey CW, Tomaras AP, Connerly PL, Tolmasky ME, Crosa JH, Actis LA. The siderophore-mediated iron
acquisition systems of Acinetobacter baumannii ATCC 19606 and Vibrio anguillarum 775 are structurally and functionally related. Microbiology. 2004; 150(Pt 11):3657-67.
11. Tomaras AP, Dorsey CW, Edelmann RE, Actis LA. Attachment to and biofilm formation on abiotic surfaces by Acinetobacter baumannii: involvement of a novel chaperone-usher pili assembly system. Microbiology. 2003; 149(Pt 12):3473-84.
12. Choi CH, Lee EY, Lee YC, Park TI, Kim HJ, Hyun SH, et al. Outer membrane protein 38 of Acinetobacter baumannii localizes to the mitochondria and induces apoptosis of epithelial cells. Cellular microbiology. 2005; 7(8):1127-38.
13. Vasil ML, Tomaras AP, Pritchard AE. Identification and Evaluation of Twin-Arginine Translocase Inhibitors. Antimicrobial Agents and Chemotherapy. 2012; 56(12):6223-34.
14. Echenique JR, Arienti H, Tolmasky ME, Read RR, Staneloni RJ, Crosa JH, et al. Characterization of a high-affinity iron transport system in Acinetobacter baumannii. Journal of Bacteriology. 1992; 174(23):7670-9.
15. Sahu PK, Iyer PS, Gaikwad MB, Talreja SC, Pardesi KR, Chopade BA. An MFS Transporter-Like ORF from MDR Acinetobacter baumannii AIIMS 7 IsAssociated with Adherence and Biofilm Formation on Biotic/Abiotic Surface. International Journal of Microbiology. 2012.
16. Vallenet D, Nordmann P, Barbe V, Poirel L, Mangenot S, Bataille E, et al. Comparative Analysis of Acinetobacters: Three Genomes for Three Lifestyles. PLoS ONE. 2008; 3(3). P
17. Weber BS, Miyata ST, Iwashkiw JA, Mortensen BL, Skaar EP, Pukatzki S, et al. Genomic and Functional Analysis of the Type VI Secretion System in Acinetobacter. PLoS One. 2013; 8(1):e55142.
18. Harding CM, Tracy EN, Carruthers MD, Rather PN, Actis LA, Munson RS. Acinetobacter baumannii Strain M2 Produces Type IV Pili Which Play a Role in Natural Transformation and Twitching Motility but Not Surface-Associated Motility. mBio. 2013; 4(4).
19. Smith MG, Gianoulis TA, Pukatzki S, Mekalanos JJ, Ornston LN, Gerstein M, et al. New insights into Acinetobacter baumannii pathogenesis revealed by highdensity pyrosequencing and transposon mutagenesis. Genes & Development. 2007; 21(5):601-14.
20. Sahl JW, Johnson JK, Harris AD, Phillippy AM, Hsiao WW, Thom KA, et al. Genomic comparison of multi-drug resistant invasive and colonizing Acinetobacter baumannii isolated from diverse human body sites reveals genomic plasticity. BMC Genomics. 2011;12:291.
21. Henry R, Vithanage N, Harrison P, Seemann T, Coutts S, Moffatt JH, et al. Colistin-Resistant, Lipopolysaccharide- Deficient Acinetobacter baumannii Responds to Lipopolysaccharide Loss through Increased Expression of Genes Involved in the Synthesis and Transport of Lipoproteins, Phospholipids, and
Poly-?- 1,6-N-Acetylglucosamine. Antimicrobial Agents and Chemotherapy. 2012;
56(1):59-69.
22. Marti S, Nait Chabane Y, Alexandre S, Coquet L, Vila J, Jouenne T, et al. Growth of Acinetobacter baumannii in Pellicle Enhanced the Expression of Potential Virulence Factors. PLoS ONE. 2011;6(10).
23. Zhu L, Yan Z, Zhang Z, Zhou Q, Zhou J, Wakeland EK, et al. Complete Genome Analysis of Three Acinetobacter baumannii Clinical Isolates in China for Insight into the Diversification of Drug Resistance Elements. PLoS ONE. 2013; 8(6).
24. Miranda MC, Perez F, Zuluaga T, et al. Antimicrobial resistance in gram negative bacteria isolated from intensive care units of Colombian hospitals, WHONET 2003, 2004 and 2005. Biomedica 2006; 26(3):424-33.
25. Groisman EA, Ochman H. Pathogenicity islands: bacterial evolution in quantum leaps. Cell. 1996; 87(5):791-4.
26. Dijkshoorn L, Nemec A, Seifert H. An increasing threat in hospitals: multidrugresistant Acinetobacter baumannii. Nature reviews Microbiology. 2007; 5(12):939- 51.
27. Schmidt H, Hensel M. Pathogenicity Islands in Bacterial Pathogenesis. Clinical Microbiology Reviews. 2004; 17(1):14- 56.
28. Backert S, Meyer TF. Type IV secretion systems and their effectors in bacterial pathogenesis. Current opinion in microbiology. 2006; 9(2):207-17.
29. Gohl O, Friedrich A, Hoppert M, Averhoff B. The thin pili of Acinetobacter sp. strain BD413 mediate adhesion to biotic and abiotic surfaces. Applied and Environmental Microbiology. 2006; 72(2):1394-401.
30. Fournier PE, Vallenet D, Barbe V, Audic S, Ogata H, Poirel L, et al. Comparative genomics of multidrug resistance in Acinetobacter baumannii. PLoS Genetics. 2006; 2(1):e7.
31. Segal G, Feldman M, Zusman T. The Icm/Dot type-IV secretion systems of Legionella pneumophila and Coxiella burnetii. FEMS microbiology reviews. 2005; 29(1):65-81.
32. Vogel JP, Andrews HL, Wong SK, Isberg RR. Conjugative Transfer by the Virulence System of Legionella pneumophila. Science. 1998; 279(5352):873-6.
33. Vincent CD, Friedman JR, Jeong KC, Buford EC, Miller JL, Vogel JP. Identification of the core transmembrane complex of the Legionella Dot/Icm type IV secretion system. Molecular Microbiology. 2006; 62(5):1278-91.
34. Ou HY, Chen LL, Lonnen J, Chaudhuri RR, Thani AB, Smith R, et al. A novel strategy for the identification of
genomic islands by comparative analysis of the contents and contexts of tRNA sites in closely related bacteria. Nucleic Acids Research. 2006; 34(1):e3.
35. Hacker J, Carniel E. Ecological fitness, genomic islands and bacterial pathogenicity. A Darwinian view of the evolution of microbes. EMBO reports. 2001; 2(5):376-81.
36. Mantri Y, Williams KP. Islander: a database of integrative islands in prokaryotic genomes, the associated integrases and their DNA site specificities. Nucleic Acids Research. 2004; 32(Database issue):D55-8.
37. Hsiao W, Wan I, Jones SJ, Brinkman FS. IslandPath: aiding detection of genomic islands in prokaryotes. Bioinformatics. 2003;19(3):418-20.
38. Grohmann E, Muth G, Espinosa M. Conjugative plasmid transfer in grampositive bacteria. Microbiology and Molecular Biology Reviews: MMBR. 2003; 67(2):277-301
39. Schroder G, Lanka E. The mating pair formation system of conjugative plasmids-A versatile secretion machinery for transfer of proteins and DNA. Plasmid. 2005; 54(1):1-25.
40. Cascales E, Christie PJ. The versatile bacterial type IV secretion systems. Nature reviews Microbiology. 2003; 1(2):137-49.
41. Sexton JA, Vogel JP. Type IVB secretion by intracellular pathogens. Traffic (Copenhagen, Denmark). 2002; 3(3):178- 85.
42. Karnholz A, Hoefler C, Odenbreit S, Fischer W, Hofreuter D, Haas R. Functional and topological characterization of novel components of the comB DNA transformation competence system in Helicobacter pylori. Journal of Bacteriology. 2006; 188(3):882-93.
43. Backert S, Kwok T, Konig W. Conjugative plasmid DNA transfer in Helicobacter pylori mediated by chromosomallyencoded relaxase and TraG-like proteins. Microbiology. 2005; 151(Pt 11):3493-503.
44. Miyamoto H, Yoshida S, Taniguchi H, Shuman HA. Virulence conversion of Legionella pneumophila by conjugal transfer of chromosomal DNA. Journal of Bacteriology. 2003; 185(22):6712-8.
45. Dorsey CW, Beglin MS, Actis LA. Detection and analysis of iron uptake components expressed by Acinetobacter baumannii clinical isolates. Journal of clinical microbiology. 2003; 41(9):4188- 93.
46. Bassili A, Fitzpatrick C, Qadeer E, Fatima R, Floyd K, Jaramillo E. A systematic review of the effectiveness of hospitaland ambulatory-based management of multidrug-resistant tuberculosis. The American journal of tropical medicine and hygiene. 2013; 89(2):271-80.
47. Sommer R, Joachim I, Wagner S, Titz A. New approaches to control infections: antibiofilm strategies against gram-negative bacteria. Chimia. 2013; 67(4):286-90.
48. Jaramillo EL. Resistencia bacteriana a los antibióticos en la Unidad de Cuidados Intensivos, Hospital de Caldas, 1992- 1994. Colombia Médica. 1996; 27(2):69- 76.
49. Pa ine K, Flowe r DR. Ba c t e r i a l bioinformatics: pathogenesis and the genome. Journal of molecular
microbiology and biotechnology. 2002; 4(4):357-65.
50. Haley RW. Measuring the costs of nosocomial infections: Methods for estimating economic burden on the
hospital. The American Journal of Medicine. 1991; 91(suppl 2):S32-S8.
51. Grant JR, Stothard P. The CGView Server: a comparative genomics tool for circular genomes. Nucleic Acids Research. 2008; 36(suppl 2):W181-W4.
52. Karlin S. Detecting anomalous gene clusters and pathogenicity islands in diverse bacterial genomes. Trends in Microbiology. 2001; 9(7):335-43.
53. Tu Q, Ding D. Detecting pathogenicity islands and anomalous gene clusters by iterative discriminant analysis. FEMS microbiology letters. 2003; 221(2):269-75.
54. Abbott JC, Aanensen DM, Rutherford K, Butcher S, Spratt BG. WebACT-an online companion for the Artemis Comparison Tool. Bioinformatics. 2005; 21(18):3665- 6.
55. Carver TJ, Rutherford KM, Berriman M, Rajandream MA, Barrell BG, Parkhill J. ACT: the Artemis Comparison Tool. Bioinformatics. 2005; 21(16):3422-3.
56. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. Journal of molecular biology. 1990; 215(3):403-10.
57. Saenz HL, Engel P, Stoeckli MC, Lanz C, Raddatz G, Vayssier-Taussat M, et al. Genomic analysis of Bartonella identifies type IV secretion systems as host adaptability factors. Nature genetics. 2007;39(12):1469-
76.
58. Rutherford K, Parkhill J, Crook J, Horsnell T, Rice P, Rajandream MA, et al. Artemis: sequence visualization and annotation. Bioinformatics. 2000; 16(10):944-5.
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