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References

  1. Adams MD, Nickel GC, Bajaksouzian S, Lavender H, Murthy AR, Jacobs MR, et al. 2009. Resistance to colistin in Acinetobacter baumannii associated with mutations in the PmrAB two-component system. Antimicrob. Agents Chemother. 53:3628-3634.
    Pubmed PMC CrossRef
  2. Cannatelli A, D’Andrea MM, Giani T, Di Pilato V, Arena F, Ambretti S, et al. 2013. In vivo emergence of colistin resistance in Klebsiella pneumoniae producing KPC-type carbapenemases mediated by insertional inactivation of the PhoQ/PhoP mgrB regulator. Antimicrob. Agents Chemother. 57: 5521-5526.
    Pubmed PMC CrossRef
  3. Cannatelli A, Di Giani T, D’Andrea MM, Pilato VD, Arena F, Conte V, et al. 2014. MgrB inactivation is a common mechanism of colistin resistance in KPC-producing Klebsiella pneumoniae of clinical origin. Antimicrob. Agents Chemother. 58: 5696-5703.
    Pubmed PMC CrossRef
  4. Cannatelli A, Di Pilato V, Giani T, Arena F, Ambretti S, Gaibani P, et al. 2014. In vivo evolution to colistin resistance by PmrB sensor kinase mutation in KPC-producing Klebsiella pneumoniae is associated with low-dosage colistin treatment. Antimicrob. Agents Chemother. 58: 4399-4403.
    Pubmed PMC CrossRef
  5. Cheng HY, Chen YF, Peng HL. 2010. Molecular characterization of the PhoPQ-PmrD-PmrAB-mediated pathway regulating polymyxin B resistance in Klebsiella pneumoniae CG43. J. Biomed. Sci. 17: 60.
    Pubmed PMC CrossRef
  6. Choi MJ, Ko KS. 2015. Loss of hypermucoviscosity and increased fitness cost in colistin-resistant Klebsiella pneumoniae sequence type 23 strains. Antimicrob. Agents Chemother. 59:6763-6773.
    Pubmed PMC CrossRef
  7. Clements A, Tull D, Jenney AW, Farn JL, Kim SH, Bishop RE, et al. 2007. Secondary acylation of Klebsiella pneumoniae lipopolysaccharide contributes to sensitivity to antibacterial peptides. J. Biol. Chem. 282: 15569-15577.
    Pubmed PMC CrossRef
  8. Clinical and Laboratory Standards Institute. 2015. Performance Standards for Antimicobial Susceptibility Testing. Wayne, PA, USA.
  9. Diancourt L, Passet V, Verhoet J, Grimont PA, Brisse S. 2005. Multilocus sequence typing of Klebsiella pneumoniae nosocomial isolates. J. Clin. Microbiol. 43: 4178-4182.
    Pubmed PMC CrossRef
  10. Edwards RA, Keller LH, Schifferli DM. 1998. Improved allelic exchange vectors and their use to analyze 987P fimbria gene expression. Gene 207: 149-157.
    CrossRef
  11. Falagas ME, Kasiakoul SK. 2005. Colistin: the revival of polymyxins for the management of multidrug-resistant gramnegative bacterial infections. Clin. Infect. Dis. 40: 1333-1341.
    Pubmed CrossRef
  12. Falagas ME, Lourida P, Poulikakos P, Rafailidis PI, Tansarli GS. 2014. Antibiotic treatment of infections due to carbapenem-resistant Enterobacteriaceae: systematic evaluation of the available evidence. Antimicrob. Agents Chemother. 58:654-663.
    Pubmed PMC CrossRef
  13. Goel G, Hmar L, Sarkar De M, Bhattacharya S, Chandy M. 2014. Colistin-resistant Klebsiella pneumoniae: report of a cluster of 24 cases from a new oncology center in eastern India. Infect. Control Hosp. Epidemiol. 35: 1076-1077.
    Pubmed CrossRef
  14. Jayol A, Nordmann P, Brink A, Poirel L. 2015. Heteroresistance to colistin in Klebsiella pneumoniae associated with alterations in the PhoPQ regulatory system. Antimicrob. Agents Chemother. 59: 2780-2784.
    Pubmed PMC CrossRef
  15. Jayol A, Poirel L, Brink A, Vilegas MV, Yilmaz M, Nordmann P. 2014. Resistance to colistin associated with a single amino acid change in protein PmrB among Klebsiella pneumoniae isolates of worldwide origin. Antimicrob. Agents Chemother. 58: 4762-4766.
    Pubmed PMC CrossRef
  16. Lee JH, Lee HJ, Shin MK, Ryu WS. 2004. Versatile PCRmediated insertion or deletion mutagenesis. Biotechniques 36:398-400.
    Pubmed
  17. Li J, Nation RL, Milne RW, Turnidge JD, Coulthard K. 2005. Evaluation of colistin as an agent against multi-resistant gram-negative bacteria. Int. J. Antimicrob. Agents 25: 11-25.
    Pubmed CrossRef
  18. Llobet E, Campos MA, Giménez P, Moranta D, Bengoechea JA. 2011. Analysis of the networks controlling the antimicrobialpeptidedependent induction of Klebsiella pneumoniae virulence factors. Infect. Immun. 79: 3718-3732.
    Pubmed PMC CrossRef
  19. Mitrophanov AY, Jewett MW, Hadley TJ, Groisman EA. 2008. Evolution and dynamics of regulatory architectures controlling polymyxin B resistance in enteric bacteria. PLoS Genet. 4: e1000233.
    Pubmed PMC CrossRef
  20. Monaco M, Giani T, Raffone M, Arena F, Garcia-Fernandez A, Pollini S, et al. 2014. Colistin resistance superimposed to endemic carbapenem-resistant Klebsiella pneumoniae: a rapidly evolving problem in Italy. Euro. Surveill. 19: pii=20939.
    Pubmed CrossRef
  21. Nation RL, Li J. 2009. Colistin in 21st century. Curr. Opin. Infect. Dis. 22: 535-543.
    Pubmed PMC CrossRef
  22. Nordmann P, Naas T, Poirel L. 2011. Global spread of carbapenemase-producing Enterobacteriaceae. Emerg. Infect. Dis. 17: 1791-1798.
    Pubmed PMC CrossRef
  23. Olaitan AO, Diene SM, Kempf M, Berranzeg M, Bakour S, Gupta SK, et al. 2014. Worldwide emergence of colistin resistance in Klebsiella pneumoniae from healthy humans and patients in Lao PDR, Thailand, Israel, Nigeria and France owing to inactivation of the PhoP/PhoQ regulator mgrB: an epidemiological and molecular study. Int. J. Antimicrob. Agents 44: 500-507.
    Pubmed CrossRef
  24. Podschun R, Ullmann U. 1998. Klebsiella spp. as nosocomial pathogens: epidemiology, taxonomy, typing methods, and pathogenicity factors. Clin. Microbiol. Rev. 11: 589-603.
    Pubmed PMC
  25. Poirel L, Jayol A, Bontron S, Villegas MV, Ozdamar M, Türkoglu S, Nordmann P. 2015. The mgrB gene as a key target for acquired resistance to colistin in Klebsiella pneumoniae. J. Antimicrob. Chemother. 70: 75-80.
    Pubmed CrossRef
  26. Snitkin ES, Zelazny AM, Thomas PJ, Stock F; NISC Comparative Sequencing Program Group, Henderson DK, Palmore TN, Segre JA. 2012. Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing. Sci. Transl. Med. 4: 148ra116.
    Pubmed PMC CrossRef
  27. Song JH, Ko KS. 2008. Detection of essential genes in Streptococcus pneumoniae using bioinformatics and allelic replacement mutagenesis. Methods Mol. Biol. 416: 401-408.
    Pubmed CrossRef
  28. Suh JY, Son JS, Chung DR, Peck KR, Ko KS, Song JH. 2010. Nonclonal emergence of colistin-resistant Klebsiella pneumoniae isolates from blood samples in South Korea. Antimicrob. Agents Chemother. 54: 560-562.
    Pubmed PMC CrossRef
  29. Winfield MD, Groisman EA. 2004. Phenotypic differences between Salmonella and Escherichia coli resulting from the disparate regulation of homologous genes. Proc. Natl. Acad. Sci. USA 101: 17162-17167.
    Pubmed PMC CrossRef
  30. Wright MS, Suzuki Y, Jones MB, Marshall SH, Rudin SD, van Duin D, et al. 2015. Genomic and transcriptomic analyses of colistin-resistant clinical isolates of Klebsiella pneumoniae reveal multiple pathways of resistance. Antimicrob. Agents Chemother. 59: 536-543.
    Pubmed PMC CrossRef

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Article

Research article

J. Microbiol. Biotechnol. 2016; 26(9): 1620-1628

Published online September 28, 2016 https://doi.org/10.4014/jmb.1604.04016

Copyright © The Korean Society for Microbiology and Biotechnology.

Pathways Regulating the pbgP Operon and Colistin Resistance in Klebsiella pneumoniae Strains

Myung-Jin Choi 1, Sunju Kim 1 and Kwan Soo Ko 1*

Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of Korea

Received: April 7, 2016; Accepted: May 27, 2016

Abstract

In this study, we investigated colistin resistance mechanisms associated with the regulation of
the pbgP operon in Klebsiella pneumoniae, using four isogenic pairs of colistin-susceptible
strains and their colistin-resistant derivatives and two colistin-resistant clinical isolates.
Amino acid sequence alterations of PhoPQ, PmrAB, and MgrB were investigated, and mRNA
expression levels of phoQ, pmrB, pmrD, and pbgP were measured using quantitative real-time
PCR. The phoQ and pmrB genes were deleted from two colistin-resistant derivatives, 134R and
063R. We found that phoQ, pmrD, and pbgP were significantly upregulated in all colistinresistant
derivatives. However, pmrB was significantly upregulated in only two colistinresistant
derivatives and one clinical strain. pmrB was not overexpressed in the other strains.
The minimum inhibitory concentration of colistin was drastically lower in both phoQ- and
pmrB-deleted mutants from a colistin-resistant derivative (134R) that was overexpressing phoQ
and pmrB. However, colistin susceptibility was restored only in a phoQ-deleted mutant from a
colistin-resistant derivative (063R) without overexpression of pmrB. In conclusion, two
different regulations of the pbgP operon may associate with the development of colistinresisant
K. pneumoniae.

Keywords: Colistin resistance, Klebsiella pneumoniae, two-component regulatory systems

References

  1. Adams MD, Nickel GC, Bajaksouzian S, Lavender H, Murthy AR, Jacobs MR, et al. 2009. Resistance to colistin in Acinetobacter baumannii associated with mutations in the PmrAB two-component system. Antimicrob. Agents Chemother. 53:3628-3634.
    Pubmed KoreaMed CrossRef
  2. Cannatelli A, D’Andrea MM, Giani T, Di Pilato V, Arena F, Ambretti S, et al. 2013. In vivo emergence of colistin resistance in Klebsiella pneumoniae producing KPC-type carbapenemases mediated by insertional inactivation of the PhoQ/PhoP mgrB regulator. Antimicrob. Agents Chemother. 57: 5521-5526.
    Pubmed KoreaMed CrossRef
  3. Cannatelli A, Di Giani T, D’Andrea MM, Pilato VD, Arena F, Conte V, et al. 2014. MgrB inactivation is a common mechanism of colistin resistance in KPC-producing Klebsiella pneumoniae of clinical origin. Antimicrob. Agents Chemother. 58: 5696-5703.
    Pubmed KoreaMed CrossRef
  4. Cannatelli A, Di Pilato V, Giani T, Arena F, Ambretti S, Gaibani P, et al. 2014. In vivo evolution to colistin resistance by PmrB sensor kinase mutation in KPC-producing Klebsiella pneumoniae is associated with low-dosage colistin treatment. Antimicrob. Agents Chemother. 58: 4399-4403.
    Pubmed KoreaMed CrossRef
  5. Cheng HY, Chen YF, Peng HL. 2010. Molecular characterization of the PhoPQ-PmrD-PmrAB-mediated pathway regulating polymyxin B resistance in Klebsiella pneumoniae CG43. J. Biomed. Sci. 17: 60.
    Pubmed KoreaMed CrossRef
  6. Choi MJ, Ko KS. 2015. Loss of hypermucoviscosity and increased fitness cost in colistin-resistant Klebsiella pneumoniae sequence type 23 strains. Antimicrob. Agents Chemother. 59:6763-6773.
    Pubmed KoreaMed CrossRef
  7. Clements A, Tull D, Jenney AW, Farn JL, Kim SH, Bishop RE, et al. 2007. Secondary acylation of Klebsiella pneumoniae lipopolysaccharide contributes to sensitivity to antibacterial peptides. J. Biol. Chem. 282: 15569-15577.
    Pubmed KoreaMed CrossRef
  8. Clinical and Laboratory Standards Institute. 2015. Performance Standards for Antimicobial Susceptibility Testing. Wayne, PA, USA.
  9. Diancourt L, Passet V, Verhoet J, Grimont PA, Brisse S. 2005. Multilocus sequence typing of Klebsiella pneumoniae nosocomial isolates. J. Clin. Microbiol. 43: 4178-4182.
    Pubmed KoreaMed CrossRef
  10. Edwards RA, Keller LH, Schifferli DM. 1998. Improved allelic exchange vectors and their use to analyze 987P fimbria gene expression. Gene 207: 149-157.
    CrossRef
  11. Falagas ME, Kasiakoul SK. 2005. Colistin: the revival of polymyxins for the management of multidrug-resistant gramnegative bacterial infections. Clin. Infect. Dis. 40: 1333-1341.
    Pubmed CrossRef
  12. Falagas ME, Lourida P, Poulikakos P, Rafailidis PI, Tansarli GS. 2014. Antibiotic treatment of infections due to carbapenem-resistant Enterobacteriaceae: systematic evaluation of the available evidence. Antimicrob. Agents Chemother. 58:654-663.
    Pubmed KoreaMed CrossRef
  13. Goel G, Hmar L, Sarkar De M, Bhattacharya S, Chandy M. 2014. Colistin-resistant Klebsiella pneumoniae: report of a cluster of 24 cases from a new oncology center in eastern India. Infect. Control Hosp. Epidemiol. 35: 1076-1077.
    Pubmed CrossRef
  14. Jayol A, Nordmann P, Brink A, Poirel L. 2015. Heteroresistance to colistin in Klebsiella pneumoniae associated with alterations in the PhoPQ regulatory system. Antimicrob. Agents Chemother. 59: 2780-2784.
    Pubmed KoreaMed CrossRef
  15. Jayol A, Poirel L, Brink A, Vilegas MV, Yilmaz M, Nordmann P. 2014. Resistance to colistin associated with a single amino acid change in protein PmrB among Klebsiella pneumoniae isolates of worldwide origin. Antimicrob. Agents Chemother. 58: 4762-4766.
    Pubmed KoreaMed CrossRef
  16. Lee JH, Lee HJ, Shin MK, Ryu WS. 2004. Versatile PCRmediated insertion or deletion mutagenesis. Biotechniques 36:398-400.
    Pubmed
  17. Li J, Nation RL, Milne RW, Turnidge JD, Coulthard K. 2005. Evaluation of colistin as an agent against multi-resistant gram-negative bacteria. Int. J. Antimicrob. Agents 25: 11-25.
    Pubmed CrossRef
  18. Llobet E, Campos MA, Giménez P, Moranta D, Bengoechea JA. 2011. Analysis of the networks controlling the antimicrobialpeptidedependent induction of Klebsiella pneumoniae virulence factors. Infect. Immun. 79: 3718-3732.
    Pubmed KoreaMed CrossRef
  19. Mitrophanov AY, Jewett MW, Hadley TJ, Groisman EA. 2008. Evolution and dynamics of regulatory architectures controlling polymyxin B resistance in enteric bacteria. PLoS Genet. 4: e1000233.
    Pubmed KoreaMed CrossRef
  20. Monaco M, Giani T, Raffone M, Arena F, Garcia-Fernandez A, Pollini S, et al. 2014. Colistin resistance superimposed to endemic carbapenem-resistant Klebsiella pneumoniae: a rapidly evolving problem in Italy. Euro. Surveill. 19: pii=20939.
    Pubmed CrossRef
  21. Nation RL, Li J. 2009. Colistin in 21st century. Curr. Opin. Infect. Dis. 22: 535-543.
    Pubmed KoreaMed CrossRef
  22. Nordmann P, Naas T, Poirel L. 2011. Global spread of carbapenemase-producing Enterobacteriaceae. Emerg. Infect. Dis. 17: 1791-1798.
    Pubmed KoreaMed CrossRef
  23. Olaitan AO, Diene SM, Kempf M, Berranzeg M, Bakour S, Gupta SK, et al. 2014. Worldwide emergence of colistin resistance in Klebsiella pneumoniae from healthy humans and patients in Lao PDR, Thailand, Israel, Nigeria and France owing to inactivation of the PhoP/PhoQ regulator mgrB: an epidemiological and molecular study. Int. J. Antimicrob. Agents 44: 500-507.
    Pubmed CrossRef
  24. Podschun R, Ullmann U. 1998. Klebsiella spp. as nosocomial pathogens: epidemiology, taxonomy, typing methods, and pathogenicity factors. Clin. Microbiol. Rev. 11: 589-603.
    Pubmed KoreaMed
  25. Poirel L, Jayol A, Bontron S, Villegas MV, Ozdamar M, Türkoglu S, Nordmann P. 2015. The mgrB gene as a key target for acquired resistance to colistin in Klebsiella pneumoniae. J. Antimicrob. Chemother. 70: 75-80.
    Pubmed CrossRef
  26. Snitkin ES, Zelazny AM, Thomas PJ, Stock F; NISC Comparative Sequencing Program Group, Henderson DK, Palmore TN, Segre JA. 2012. Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing. Sci. Transl. Med. 4: 148ra116.
    Pubmed KoreaMed CrossRef
  27. Song JH, Ko KS. 2008. Detection of essential genes in Streptococcus pneumoniae using bioinformatics and allelic replacement mutagenesis. Methods Mol. Biol. 416: 401-408.
    Pubmed CrossRef
  28. Suh JY, Son JS, Chung DR, Peck KR, Ko KS, Song JH. 2010. Nonclonal emergence of colistin-resistant Klebsiella pneumoniae isolates from blood samples in South Korea. Antimicrob. Agents Chemother. 54: 560-562.
    Pubmed KoreaMed CrossRef
  29. Winfield MD, Groisman EA. 2004. Phenotypic differences between Salmonella and Escherichia coli resulting from the disparate regulation of homologous genes. Proc. Natl. Acad. Sci. USA 101: 17162-17167.
    Pubmed KoreaMed CrossRef
  30. Wright MS, Suzuki Y, Jones MB, Marshall SH, Rudin SD, van Duin D, et al. 2015. Genomic and transcriptomic analyses of colistin-resistant clinical isolates of Klebsiella pneumoniae reveal multiple pathways of resistance. Antimicrob. Agents Chemother. 59: 536-543.
    Pubmed KoreaMed CrossRef