Mechanisms of Penicillin Resistance in Streptococcus pneumoniae: Targets, Gene Transfer and Mutations

  • Regine Hakenbeck
  • Dalia Denapaite
  • Patrick Maurer
Chapter

Abstract

Penicillin resistance in Streptococcus pneumoniae has been recognized in the bacterial population 40 years ago and has increased dramatically worldwide ever since. It is based on alterations of the penicillin target enzymes, the penicillin binding proteins (PBPs). In clinical isolates, horizontal gene transfer involving closely related commensal species mediates the acquisition of highly altered PBP genes, resulting in the evolution of complex mosaic structures. The identification of PBP mutations in resistant laboratory mutants has helped to reveal amino acids responsible for the decreased affinity of the target proteins, in addition to high resolution structures of PBPs from resistant clinical isolates. Moreover, non-PBP genes have been discovered that contribute to resistance.

Keywords

Hydrolysis Europe Codon Recombination Penicillin 

Notes

Acknowledgment

This work was supported by the DFG (Ha 1011/11-1) and the EU (LSHM-CT-2003-503413 and −503335).

References

  1. 1.
    Adam M, Damblon C, Jamin M et al (1991) Acyltransferase activities of the high-molecular-mass essential penicillin-binding proteins. Biochem J 279:601–604PubMedGoogle Scholar
  2. 2.
    Asahi Y, Takeuchi Y, Ubukata K (1999) Diversity of substitutions within or adjacent to ­conserved amino acid motifs of penicillin-binding protein 2x in cephalosporin-resistant Streptococcus pneumoniae isolates. Antimicrob Agents Chemother 43:1252–1255PubMedGoogle Scholar
  3. 3.
    Barcus VA, Ghanekar K, Yeo M et al (1995) Genetics of high level penicillin resistance in clinical isolates of Streptococcus pneumoniae. FEMS Microbiol Lett 126:299–303PubMedGoogle Scholar
  4. 4.
    Beall B, McEllistrem MC, Gertz RE Jr et al (2002) Emergence of a novel penicillin-nonsusceptible, invasive serotype 35B clone of Streptococcus pneumoniae within the United States. J Infect Dis 186:118–122PubMedGoogle Scholar
  5. 5.
    Cafini F, del Campo R, Alou L et al (2006) Alterations of the penicillin-binding proteins and murM alleles of clinical Streptococcus pneumoniae isolates with high-level resistance to amoxicillin in Spain. J Antimicrob Chemother 57:224–229PubMedGoogle Scholar
  6. 6.
    Carapito R, Chesnel L, Vernet T et al (2006) Pneumococcal β-lactam resistance due to a conformational change in penicillin-binding protein 2x. J Biol Chem 281:1771–1777PubMedGoogle Scholar
  7. 7.
    Carapito R, Gallet B, Zapun A et al (2006) Automated high-throughput process for site-directed mutagenesis, production, purification, and kinetic characterization of enzymes. Anal Biochem 355:110–116PubMedGoogle Scholar
  8. 8.
    Chesnel L, Carapito R, Croizé J et al (2005) Identical penicillin-binding domains in penicillin-binding proteins of Streptococcus pneumoniae clinical isolates with different levels of β-lactam resistance. Antimicrob Agents Chemother 49:2895–2902PubMedGoogle Scholar
  9. 9.
    Chesnel L, Pernot L, Lemaire D et al (2003) The structural modifications induced by the M339F substitution in PBP2x from Streptococcus pneumoniae further decreases the susceptibility to β-lactams of resistant strains. J Biol Chem 278:44448–44456PubMedGoogle Scholar
  10. 10.
    Chi F (2004) The role of viridans sterptococci in the evolution onf penicillin resistance in Streptococcus pneumonaie: genetic relationships, mosaic PBP1a genes and the price of resistance. Thesis, University of KaiserslauternGoogle Scholar
  11. 11.
    Chi F, Nolte O, Bergmann C et al (2007) Crossing the barrier: evolution and spread of a major class of mosaic pbp2x in S. pneumoniae, S. mitis and S. oralis. Int J Med Microbiol 297:503–512PubMedGoogle Scholar
  12. 12.
    Coffey TJ, Daniels M, Enright MC et al (1999) Serotype 14 variants of the Spanish penicillin-resistant serotype 9V clone of Streptococcus pneumoniae arose by large recombinational replacements of the cpsA-pbp1a region. Microbiology 145:2023–2031PubMedGoogle Scholar
  13. 13.
    Coffey TJ, Daniels M, McDougal LK et al (1995) Genetic analysis of clinical isolates of Streptococcus pneumoniae with high-level resistance to expanded-spectrum cephalosporins. Antimicrob Agents Chemother 39:1306–1313PubMedGoogle Scholar
  14. 14.
    Coffey TJ, Dowson CG, Daniels M et al (1991) Horizontal transfer of multiple penicillin-binding protein genes, and capsular biosynthetic genes, in natural populations of Streptococcus pneumoniae. Mol Microbiol 5:2255–2260PubMedGoogle Scholar
  15. 15.
    Coffey TJ, Enright MC, Daniels M et al (1998) Recombinational exchanges at the capsular polysaccharide biosynthetic locus lead to frequent serotype changes among natural isolates of Streptococcus pneumoniae. Mol Microbiol 27:73–83PubMedGoogle Scholar
  16. 16.
    Collatz E, Labia R, Gutmann L (1990) Molecular evolution of ubiquitous β-lactamases towards extended-spectrum enzymes active against newer β-lactam antibiotics. Mol Microbiol 4:1615–1620PubMedGoogle Scholar
  17. 17.
    Contreras-Martel C, hout-Gonzalez C, Martins AS et al (2009) PBP active site flexibility as the key mechanism for β-lactam resistance in pneumococci. J Mol Biol 387:899–909PubMedGoogle Scholar
  18. 18.
    Dagan R (2009) Impact of pneumococcal conjugate vaccine on infections caused by antibiotic-resistant Streptococcus pneumoniae. Clin Microbiol Infect 15(Suppl 3):16–20PubMedGoogle Scholar
  19. 19.
    De Pascale G, Lloyd AJ, Schouten JA et al (2008) Kinetic characterization of lipid II-Ala:alanyl-tRNA ligase (MurN) from Streptococcus pneumoniae using semisynthetic aminoacyl-lipid II substrates. J Biol Chem 283:34571–34579PubMedGoogle Scholar
  20. 20.
    Dessen A, Mouz N, Gordon E et al (2001) Crystal structure of PBP2x from a highly penicillin-resistant Streptococcus pneumoniae clinical isolate: a mosaic framework containing 83 mutations. J Biol Chem 276:45105–45112Google Scholar
  21. 21.
    Di Guilmi AM, Dessen A, Dideberg O et al (2003) Functional characterization of penicillin-binding protein 1b from Streptococcus pneumoniae. J Bacteriol 185:1650–1658PubMedGoogle Scholar
  22. 22.
    Di Guilmi AM, Dessen A, Dideberg O et al (2003) The glycosyltransferase domain of ­penicillin-binding protein 2a from Streptococcus pneumoniae catalyzes the polymerization of murein glycan chains. J Bacteriol 185:4418–4423PubMedGoogle Scholar
  23. 23.
    Di Guilmi AM, Mouz N, Petillot Y et al (2000) Deacylation kinetics analysis of Streptococcus pneumoniae penicillin-binding protein 2x mutants resistant to β-lactam antibiotics using electrospray ionization- mass spectrometry. Anal Biochem 10:240–246Google Scholar
  24. 24.
    Doern GV, Ferraro MJ, Brueggemann AB et al (1996) Emergence of high rates of antimicrobial resistance among viridans group streptococci in the United States. Antimicrob Agents Chemother 40:891–894PubMedGoogle Scholar
  25. 25.
    Dowson CG, Coffey TJ, Kell C et al (1993) Evolution of penicillin resistance in Streptococcus pneumoniae; the role of Streptococcus mitis in the formation of a low affinity PBP2B in S. pneumoniae. Mol Microbiol 9:635–643PubMedGoogle Scholar
  26. 26.
    Dowson CG, Hutchison A, Brannigan JA et al (1989) Horizontal transfer of penicillin-binding protein genes in penicillin-resistant clinical isolates of Streptococcus pneumoniae. Proc Natl Acad Sci USA 86:8842–8846PubMedGoogle Scholar
  27. 27.
    Dowson CG, Johnson AP, Cercenado E et al (1994) Genetics of oxacillin resistance in clinical isolates of Streptococcus pneumoniae that are oxacillin resistant and penicillin susceptible. Antimicrob Agents Chemother 38:49–53PubMedGoogle Scholar
  28. 28.
    du Plessis M, Bingen E, Klugman KP (2002) Analysis of penicillin-binding protein genes of clinical isolates of Streptococcus pneumoniae with reduced susceptibility to amoxicillin. Antimicrob Agents Chemother 46:2349–2357PubMedGoogle Scholar
  29. 29.
    du Plessis M, Smith AM, Klugman KP (2000) Analysis of penicillin-binding protein lb and 2a genes from Streptococcus pneumoniae. Microb Drug Resist 6:127–131PubMedGoogle Scholar
  30. 30.
    Edman M, Berg S, Storm P et al (2003) Structural features of glycosyltransferases synthesizing major bilayer and nonbilayer-prone membrane lipids in Acholeplasma laidlawii and Streptococcus pneumoniae. J Biol Chem 278:8420–8428PubMedGoogle Scholar
  31. 31.
    Enright MC, Spratt BG (2004) Extensive variation in the ddl gene of penicillin-resistant Streptococcus pneumoniae results from a hitchhiking effect driven by the penicillin-binding protein 2b gene. Mol Biol Evol 16:1687–1695Google Scholar
  32. 32.
    Felmingham D (2004) Comparative antimicrobial susceptibility of respiratory tract pathogens. Chemotherapy 50(Suppl 1):3–10PubMedGoogle Scholar
  33. 33.
    Ferroni A, Berche P (2001) Alterations to penicillin-binding proteins 1A, 2B and 2X amongst penicillin-resistant clinical isolates of Streptococcus pneumoniae serotype 23F from the nasopharyngeal flora of children. J Med Microbiol 50:828–832PubMedGoogle Scholar
  34. 34.
    Figueiredo AM, Austrian R, Urbaskova P et al (1995) Novel penicillin-resistant clones of Streptococcus pneumoniae in the Czech Republic and in Slovakia. Microb Drug Resist 1:71–78PubMedGoogle Scholar
  35. 35.
    Filipe SR, Severina E, Tomasz A (2002) The murMN operon: a functional link between antibiotic resistance and antibiotic tolerance in Streptococcus pneumoniae. Proc Natl Acad Sci USA 99:1550–1555PubMedGoogle Scholar
  36. 36.
    Filipe SR, Tomasz A (2000) Inhibition of the expression of penicillin-resistance in Streptococcus pneumoniae by inactivation of cell wall muropeptide branching genes. Proc Natl Acad Sci USA 97:4891–4896PubMedGoogle Scholar
  37. 37.
    Frère J-M Joris B (1985) Penicillin-sensitive enzymes in peptidoglycan biosynthesis. Crit Rev Microbiol 11:299–396Google Scholar
  38. 38.
    Garcia-Bustos J, Tomasz A (1990) A biological price of antibiotic resistance: major changes in the peptidoglycan structure of penicillin-resistant pneumococci. Proc Natl Acad Sci USA 87:5415–5419PubMedGoogle Scholar
  39. 39.
    Garcia-Bustos JF, Chait BT, Tomasz A (1987) Structure of the peptide network of pneumococcal peptidoglycan. J Biol Chem 262:15400–15405PubMedGoogle Scholar
  40. 40.
    Goffin C, Ghuysen J-M (2002) Biochemistry and comparative genomics of SxxK superfamily acyltransferases offer a clue to the mycobacterial paradox: presence of penicillin-susceptible target proteins versus lack of efficiency of penicillin as therapeutic agent. Microbiol Mol Biol Rev 66:706–738Google Scholar
  41. 41.
    Gordon E, Mouz N, Duee E et al (2000) The crystal structure of the penicillin-binding protein 2x from Streptococcus pneumoniae and its acyl-enzyme form: implication in drug resistance. J Mol Biol 299:477–485PubMedGoogle Scholar
  42. 42.
    Granizo JJ, Aguilar L, Casal J et al (2000) Streptococcus pneumoniae resistance to erythromycin and penicillin in relation to macrolide and β-lactam consumption in Spain (1979–1997). J Antimicrob Chemother 46:767–773PubMedGoogle Scholar
  43. 43.
    Grebe T, Hakenbeck R (1996) Penicillin-binding proteins 2b and 2x of Streptococcus pneumoniae are primary resistance determinants for different classes of β-lactam antibiotics. Antimicrob Agents Chemother 40:829–834PubMedGoogle Scholar
  44. 44.
    Grebe T, Paik J, Hakenbeck R (1997) A novel resistance mechanism for β-lactams in Streptococcus pneumoniae involves CpoA, a putative glycosyltransferases. J Bacteriol 179: 3342–3349PubMedGoogle Scholar
  45. 45.
    Guenzi E, Gasc AM, Sicard MA et al (1994) A two-component signal-transducing system is involved in competence and penicillin susceptibility in laboratory mutants of Streptococcus pneumoniae. Mol Microbiol 12:505–515PubMedGoogle Scholar
  46. 46.
    Gunnison JB, Fraher MA, Pelcher EA et al (1968) Penicillin-resistant variants of pneumococci. Appl Microbiol 16:311–314PubMedGoogle Scholar
  47. 47.
    Haenni M, Majcherczyk PA, Barblan JL et al (2006) Mutational analysis of class A and class B penicillin-binding proteins in Streptococcus gordonii. Antimicrob Agents Chemother 50: 4062–4069PubMedGoogle Scholar
  48. 48.
    Hakenbeck R, Briese T, Chalkley L et al (1991) Antigenic variation of penicillin-binding proteins from penicillin resistant clinical strains of Streptococcus pneumoniae. J Infect Dis 164:313–319PubMedGoogle Scholar
  49. 49.
    Hakenbeck R, Briese T, Chalkley L et al (1991) Variability of penicillin-binding proteins from penicillin-sensitive Streptococcus pneumoniae. J Infect Dis 164:307–312PubMedGoogle Scholar
  50. 50.
    Hakenbeck R, Ellerbrok H, Martin C, Morelli G, Schuster C, Severin A, Tomasz A (1993) Penicillin-binding protein 1a and 3 in Streptococcus pneumoniae: what are essential PBP’s. In: De Pedro MA, Höltje J-V, Löffelhardt W (eds) Bacterial growth and lysis metabolism and structure of the bacterial sacculus. Plenum Press, New York\London, pp 335–340Google Scholar
  51. 51.
    Hakenbeck R, Kaminski K, König A et al (1999) Penicillin-binding proteins in β-lactam-resistant Streptococcus pneumoniae. Microb Drug Resist 5:91–99PubMedGoogle Scholar
  52. 52.
    Hakenbeck R, Kohiyama M (1982) Purification of penicillin-binding protein 3 from Streptococcus pneumoniae. Eur J Biochem 127:231–236PubMedGoogle Scholar
  53. 53.
    Hakenbeck R, König A, Kern I et al (1998) Acquisition of five high-Mr penicillin-binding protein variants during transfer of high-level β-lactam resistance from Streptococcus mitis to Streptococcus pneumoniae. J Bacteriol 180:1831–1840PubMedGoogle Scholar
  54. 54.
    Hakenbeck R, Martin C, Dowson C et al (1994) Penicillin-binding protein 2b of Streptococcus pneumoniae in piperacillin-resistant laboratory mutants. J Bacteriol 176:5574–5577PubMedGoogle Scholar
  55. 55.
    Hakenbeck R, Tarpay M, Tomasz A (1980) Multiple changes of penicillin-binding proteins in penicillin-resistant clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 17:364–371PubMedGoogle Scholar
  56. 56.
    Hakenbeck R, Tornette S, Adkinson NF (1987) Interaction of non-lytic β-lactams with penicillin-binding proteins in Streptococcus pneumoniae. J Gen Microbiol 133:755–760PubMedGoogle Scholar
  57. 57.
    Halfmann A, Kovács M, Hakenbeck R et al (2007) Identification of the genes directly controlled by the response regulator CiaR in Streptococcus pneumoniae: Five out of fifteen promoters drive expression of small noncoding RNAs. Mol Microbiol 66:110–126PubMedGoogle Scholar
  58. 58.
    Hansman D (1975) Antibiotic sensitivity pattern of pneumococci relatively insensitive to penicillin and cephalosporin antibiotics. Med J Aust 2:740–742PubMedGoogle Scholar
  59. 59.
    Hansman D, Glasgow HN, Sturt J et al (1971) Pneumococci insensitive to penicillin. Nature 230:407PubMedGoogle Scholar
  60. 60.
    Henriques-Normark B (2007) Molecular epidemiology and mechanisms for antibiotic ­resistance in Streptococcus pneumoniae. In: Hakenbeck R, Chhatwal GS (eds) Molecular biology of streptococci. Horizon Press, Wymondham, pp 269–290Google Scholar
  61. 61.
    Henriqus NB, Christensson B, Sandgren A et al (2003) Clonal analysis of Streptococcus pneumoniae nonsusceptible to penicillin at day-care centers with index cases, in a region with low incidence of resistance: emergence of an invasive type 35B clone among carriers. Microb Drug Resist 9:337–344Google Scholar
  62. 62.
    Hoskins J, Matsushima P, Mullen DL et al (1999) Gene disruption studies of penicillin-binding proteins 1a, 1b and 2a in Streptococcus pneumoniae. J Bacteriol 181:6552–6555PubMedGoogle Scholar
  63. 63.
    Izdebski R, Rutschmann J, Fiett J et al (2008) Highly variable penicillin resistance determinants PBP 2x, PBP 2b, and PBP 1a in isolates of two Streptococcus pneumoniae clonal groups, Poland23F-16 and Poland6B-20. J Bacteriol 52:1021–1027Google Scholar
  64. 64.
    Jacobs MR, Koornhof HJ, Robins-Browne RM et al (1978) Emergence of multiply resistant pneumococci. N Engl J Med 299:735–740PubMedGoogle Scholar
  65. 65.
    Jamin M, Damblon C, Millier S et al (1993) Penicillin-binding protein 2x of Streptococcus pneumoniae: enzymic activities and interactions with β-lactams. Biochem J 292:735–741PubMedGoogle Scholar
  66. 66.
    Jamin M, Hakenbeck R, Frère J-M (1992) Penicillin binding protein 2x as a major contributor to intrinsic β-lactam resistance of Streptococcus pneumoniae. FEBS Lett 331:101–104Google Scholar
  67. 67.
    Job V, Carapito R, Vernet T et al (2008) Common alterations in PBP1a from resistant Streptococcus pneumoniae decrease its reactivity toward β-lactams: structural insights. J Biol Chem 283:4886–4894PubMedGoogle Scholar
  68. 68.
    Job V, Di Guilmi AM, Martin L et al (2003) Structural studies of the transpeptidase domain of PBP1a from Streptococcus pneumoniae. Acta Crystallogr D Biol Crystallogr 59:1067–1069PubMedGoogle Scholar
  69. 69.
    Jones SWF Jr, Finland M Jr (1957) Susceptibility of pneumococci to eleven antibiotics in vitro. Am J Med Sci 233:312–319PubMedGoogle Scholar
  70. 70.
    Karnezis TT, Smith A, Whittier S et al (2009) Antimicrobial resistance among isolates causing invasive pneumococcal disease before and after licensure of heptavalent conjugate pneumococcal vaccine. PLoS One 4:e5965PubMedGoogle Scholar
  71. 71.
    Kell CM, Jordens JZ, Daniels M et al (1993) Molecular epidemiology of penicillin-resistant pneumococci isolated in Nairobi, Kenya. Infect Immun 61:4382–4391PubMedGoogle Scholar
  72. 72.
    Kell CM, Sharma UK, Dowson CG et al (1993) Deletion analysis of the essentiality of penicillin-binding proteins 1A, 2B and 2X of Streptococcus pneumoniae. FEMS Microbiol Lett 106:171–175PubMedGoogle Scholar
  73. 73.
    Kislak JW, Razavi LM, Daly AK et al (1965) Susceptibility of pneumococci to nine antibiotics. Am J Med Sci 250:261–268PubMedGoogle Scholar
  74. 74.
    König A, Reinert RR, Hakenbeck R (1998) Streptococcus mitis with unusual high level resistance to β-lactam antibiotics. Microb Drug Resist 4:45–49PubMedGoogle Scholar
  75. 75.
    Kosowska K, Jacobs MR, Bajaksouzian S et al (2004) Alterations of penicillin-binding proteins 1A, 2X, and 2B in Streptococcus pneumoniae isolates for which amoxicillin MICs are higher than penicillin MICs. Antimicrob Agents Chemother 48:4020–4022PubMedGoogle Scholar
  76. 76.
    Krauß J, Hakenbeck R (1997) A mutation in the D, D-carboxypeptidase penicillin-binding protein 3 of Streptococcus pneumoniae contributes to cefotaxime resistance of the laboratory mutant C604. Antimicrob Agents Chemother 41:936–942PubMedGoogle Scholar
  77. 77.
    Krauß J, van der Linden M, Grebe T et al (1996) Penicillin-binding proteins 2x and 2b as primary PBP-targets in Streptococcus pneumoniae. Microb Drug Resist 2:183–186PubMedGoogle Scholar
  78. 78.
    Laible G, Hakenbeck R (1991) Five independent combinations of mutations can result in low-affinity penicillin-binding protein 2x of Streptococcus pneumoniae. J Bacteriol 173: 6986–6990PubMedGoogle Scholar
  79. 79.
    Laible G, Hakenbeck R (1987) Penicillin-binding proteins in β-lactam-resistant laboratory mutants of Streptococcus pneumoniae. Mol Microbiol 1:355–363PubMedGoogle Scholar
  80. 80.
    Laible G, Spratt BG, Hakenbeck R (1991) Inter-species recombinational events during the evolution of altered PBP 2x genes in penicillin-resistant clinical isolates of Streptococcus pneumoniae. Mol Microbiol 5:1993–2002PubMedGoogle Scholar
  81. 81.
    Lee NY, Song JH, Kim S et al (2001) Carriage of antibiotic-resistant pneumococci among Asian children: a multinational surveillance by the Asian Network for Surveillance of Resistant Pathogens (ANSORP). Clin Infect Dis 32:1463–1469PubMedGoogle Scholar
  82. 82.
    Liu HH, Tomasz A (1985) Penicillin tolerance in multiply drug-resistant natural isolates of Streptococcus pneumoniae. J Infect Dis 152:365–372PubMedGoogle Scholar
  83. 83.
    Lloyd AJ, Gilbey AM, Blewett AM et al (2008) Characterization of tRNA-dependent peptide bond formation by MurM in the synthesis of Streptococcus pneumoniae peptidoglycan. J Biol Chem 283:6402–6417PubMedGoogle Scholar
  84. 84.
    Lu W-P, Kincaid E, Sun Y et al (2001) Kinetics of β-lactam interactions with penicillin-susceptible and -resistant penicillin-binding protein 2x proteins from Streptococcus pneumoniae. Involvement of acylation and deacylation in β-lactam resistance. J Biol Chem 276:31494–31501PubMedGoogle Scholar
  85. 85.
    Maiden MCJ, Bygraves JA, Feil E et al (1998) Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms. Proc Natl Acad Sci USA 95:3140–3145PubMedGoogle Scholar
  86. 86.
    Marchisio P, Esposito S, Schito GC et al (2002) Nasopharyngeal carriage of Streptococcus pneumoniae in healthy children: implications for the use of heptavalent pneumococcal conjugate vaccine. Emerg Infect Dis 8:479–484PubMedGoogle Scholar
  87. 87.
    Marimon JM, Perez-Trallero E, Ercibengoa M et al (2006) Molecular epidemiology and variants of the multidrug-resistant Streptococcus pneumoniae Spain14-5 international clone among Spanish clinical isolates. J Antimicrob Chemother 57:654–660PubMedGoogle Scholar
  88. 88.
    Marra A, Asundi J, Bartilson M et al (2002) Differential fluorescence induction analysis of Streptococcus pneumoniae identifies genes involved in pathogenesis. Infect Immun 70: 1422–1433PubMedGoogle Scholar
  89. 89.
    Martin C, Sibold C, Hakenbeck R (1992) Relatedness of penicillin-binding protein 1a genes from different clones of penicillin-resistant Streptococcus pneumoniae isolated in South Africa and Spain. EMBO J 11:3831–3836PubMedGoogle Scholar
  90. 90.
    Marton A, Gulyas M, Muñóz R et al (1991) Extremely high incidence of antibiotic resistance in clinical isolates of Streptococcus pneumoniae in Hungary. J Infect Dis 163:542–548PubMedGoogle Scholar
  91. 91.
    Mascher T, Heintz M, Zähner D et al (2006) The CiaRH system of Streptococcus pneumoniae prevents lysis during stress induced by treatment with cell wall inhibitors and mutations in pbp2x involved in β-lactam resistance. J Bacteriol 188:1959–1968PubMedGoogle Scholar
  92. 92.
    Mascher T, Merai M, Balmelle N et al (2003) The Streptococcus pneumoniae cia regulon: CiaR target sites and transcription profile analysis. J Bacteriol 185:60–70PubMedGoogle Scholar
  93. 93.
    Matsuhashi M, Ishino F, Nakagawa J et al (1984) Functional biosynthesis of cell wall peptidoglycan by polymorphic bifunctional polypeptides. Penicillin-binding protein 1Bs of Escherichia coli with activities of transglycosylase and transpeptidase. J Biol Chem 259:13937–13946PubMedGoogle Scholar
  94. 94.
    Maurer P, Koch B, Zerfaß I et al (2008) Penicillin-binding protein 2x of Streptococcus pneumoniae: three new mutational pathways for remodelling an essential enzyme into a resistance determinant. J Mol Biol 376:1403–1416PubMedGoogle Scholar
  95. 95.
    McDougal LK, Rasheed JK, Biddle JW et al (1995) Identification of multiple clones of extended-spectrum cephalosporin-resistant Streptococcus pneumoniae isolates in the United States. Antimicrob Agents Chemother 39:2282–2288PubMedGoogle Scholar
  96. 96.
    McGee L, Klugman K, Tomasz A (2000) Serotypes and clones of antibiotic-resistanct pneumococci. In: Tomasz A (ed) Streptococcus pneumoniae: molecular biology and mechanisms of disease. Mary Ann Liebert, Larchmont, pp 375–379Google Scholar
  97. 97.
    McGee L, McDougal L, Zhou J et al (2001) Nomenclature of major antimicrobial-resistant clones of Streptococcus pneumoniae defined by the Pneumococcal Molecular Epidemiological Network (PMEN). J Clin Microbiol 39:2565–2571PubMedGoogle Scholar
  98. 98.
    Morlot C, Noirclerc-Savoye M, Zapun A et al (2004) The D, D-carboxypeptidase PBP3 organizes the division process of Streptococcus pneumoniae. Mol Microbiol 51:1641–1648PubMedGoogle Scholar
  99. 99.
    Mouz N, Di Guilmi AM, Gordon E et al (1999) Mutations in the active site of penicillin-binding protein PBP2x from Streptococcus pneumoniae. Role in the specificity for β-lactam antibiotics. J Biol Chem 274:19175–19180PubMedGoogle Scholar
  100. 100.
    Mouz N, Gordon E, Di Guilmi D-M et al (1998) Identification of a structural determinant for resistance to β-lactam antibiotics in Gram-positive bacteria. Proc Natl Acad Sci USA 95:13403–13406PubMedGoogle Scholar
  101. 101.
    Muñóz R, Coffey TJ, Daniels M et al (1991) Intercontinental spread of a multiresistant clone of serotype 23F Streptococcus pneumoniae. J Infect Dis 164:302–306PubMedGoogle Scholar
  102. 102.
    Muñóz R, Dowson CG, Daniels M et al (1992) Genetics of resistance to third-generation cephalosporins in clinical isolates of Streptococcus pneumoniae. Mol Microbiol 6: 2461–2465PubMedGoogle Scholar
  103. 103.
    Nagai K, Davies TA, Jacobs MR et al (2002) Effects of amino acid alterations in penicillin-binding proteins (PBPs) 1a, 2b, and 2x on PBP affinities of penicillin, ampicillin, amoxicillin, cefditoren, cefuroxime, cefprozil, and cefaclor in 18 clinical isolates of penicillin-susceptible, -intermediate, and -resistant pneumococci. Antimicrob Agents Chemother 46:1273–1280PubMedGoogle Scholar
  104. 104.
    Negri MC, Morosini MI, Baquero MR et al (2002) Very low cefotaxime concentrations select for hypermutable Streptococcus pneumoniae populations. Antimicrob Agents Chemother 46:528–530PubMedGoogle Scholar
  105. 105.
    Nichol KA, Zhanel GG, Hoban DJ (2002) Penicillin-binding protein 1A, 2B, and 2X alterations in Canadian isolates of penicillin-resistant Streptococcus pneumoniae. Antimicrob Agents Chemother 46:3261–3264PubMedGoogle Scholar
  106. 106.
    Pagliero E, Chesnel L, Hopkins J et al (2004) Biochemical characterization of Streptococcus pneumoniae penicillin-binding protein 2b and its implication in β-lactam resistance. Antimicrob Agents Chemother 48:1848–1855PubMedGoogle Scholar
  107. 107.
    Paik J, Kern I, Lurz R et al (1999) Mutational analysis of the Streptococcus pneumoniae bimodular class A penicillin-binding proteins. J Bacteriol 181:3852–3856PubMedGoogle Scholar
  108. 108.
    Pallares R, Fenoll A, Linares J (2003) The epidemiology of antibiotic resistance in Streptococcus pneumoniae and the clinical relevance of resistance to cephalosporins, macrolides and quinolones. Int J Antimicrob Agents 22(Suppl 1):S15–S24PubMedGoogle Scholar
  109. 109.
    Percheson PB, Bryan LE (1980) Penicillin-binding components of penicillin-susceptible and -resistant strains of Streptococcus pneumoniae. Antimicrob Agents Chemother 12:390–396Google Scholar
  110. 110.
    Pernot L, Chesnel L, Le Gouellec A et al (2004) A PBP2x from a clinical isolate of Streptococcus pneumoniae exhibits an alternative mechanism for reduction of susceptibility to β-lactam antibiotics. J Biol Chem 279:16463–16470PubMedGoogle Scholar
  111. 111.
    Polonelli L, Morace G (1986) Reevaluation of the yeast killer phenomenon. J Clin Microbiol 24:866–869PubMedGoogle Scholar
  112. 112.
    Reichmann P, König A, Liñares J et al (1997) A global gene pool for high-level cephalosporin resistance in commensal Streptococcus spp. and Streptococcus pneumoniae. J Infect Dis 176:1001–1012PubMedGoogle Scholar
  113. 113.
    Reichmann P, Varon E, Günther E et al (1995) Penicillin-resistant Streptococcus pneumoniae in Germany: genetic relationship to clones from other European countries. J Med Microbiol 43:377–385PubMedGoogle Scholar
  114. 114.
    Reinert RR, Ringelstein A, van der Linden M et al (2005) Molecular epidemiology of macrolide-resistant Streptococcus pneumoniae isolates in Europe. J Clin Microbiol 43: 1294–1300PubMedGoogle Scholar
  115. 115.
    Rieux V, Carbon C, Zzoulay-Dupuis E (2001) Complex relationship between acquisition of β-lactam resistance and loss of virulence in Streptococcus pneumoniae. J Infect Dis 184:66–72PubMedGoogle Scholar
  116. 116.
    Rohrer S, Berger-Bächi B (2003) FemABX peptidyl transferases: a link between branched-chain cell wall peptide formation and β-lactam resistance in gram-positive cocci. Antimicrob Agents Chemother 47:837–846PubMedGoogle Scholar
  117. 117.
    Rutschmann J, Maurer P, Hakenbeck R (2007) Detection of penicillin-binding proteins. In: Hakenbeck R, Chhatwal GS (eds) Molecular biology of streptococci. Horizon Bioscience, Wymondham, pp 537–542Google Scholar
  118. 118.
    Sa-Leao R, Vilhelmsson SE, de Lencastre H et al (2002) Diversity of penicillin-nonsusceptible Streptococcus pneumoniae circulating in Iceland after the introduction of penicillin-resistant clone Spain(6B)-2. J Infect Dis 186:966–975PubMedGoogle Scholar
  119. 119.
    Sanbongi Y, Ida T, Ishikawa M et al (2004) Complete sequences of six penicillin-binding protein genes from 40 Streptococcus pneumoniae clinical isolates collected in Japan. Antimicrob Agents Chemother 48:2244–2250PubMedGoogle Scholar
  120. 120.
    Schuster C, Dobrinski B, Hakenbeck R (1990) Unusual septum formation in Streptococcus pneumoniae mutants with an alteration in the D, D-carboxypeptidase penicillin-binding protein 3. J Bacteriol 172:6499–6505PubMedGoogle Scholar
  121. 121.
    Sebert ME, Palmer LM, Rosenberg M et al (2002) Microarray-based identification of htrA, a Streptococcus pneumoniae gene that is regulated by the CiaRH two-component system and contributes to nasopharyngeal colonization. Infect Immun 70:4059–4067PubMedGoogle Scholar
  122. 122.
    Selakovitch-Chenu L, Seroude L, Sicard AM (1993) The role of penicillin-binding protein 3 (PBP 3) in cefotaxime resistance in Streptococcus pneumoniae. Mol Gen Genet 239:77–80PubMedGoogle Scholar
  123. 123.
    Severin A, Figueiredo AMS, Tomasz A (1996) Separation of abnormal cell wall composition from penicillin resistance through genetic transformation of Streptococcus pneumoniae. J Bacteriol 178:1788–1792PubMedGoogle Scholar
  124. 124.
    Severin A, Schuster C, Hakenbeck R et al (1992) Altered murein composition in a DD-carboxypeptidase mutant of Streptococcus pneumoniae. J Bacteriol 174:5125–5155Google Scholar
  125. 125.
    Severin A, Tomasz A (1996) Naturally occurring peptidoglycan variants of Streptococcus pneumoniae. J Bacteriol 178:168–174PubMedGoogle Scholar
  126. 126.
    Sibold C, Henrichsen J, König A et al (1994) Mosaic pbpX genes of major clones of penicillin-resistant Streptococcus pneumoniae have evolved from pbpX genes of a penicillin-sensitive Streptococcus oralis. Mol Microbiol 12:1013–1023PubMedGoogle Scholar
  127. 127.
    Sifaoui F, Kitzis M-D, Gutmann L (1996) In vitro selection of one-step mutants of Streptococcus pneumoniae resistant to different oral β-lactam antibiotics is associated with alterations of PBP2x. Antimicrob Agents Chemother 40:152–156PubMedGoogle Scholar
  128. 128.
    Sjöstrom K, Spindler C, Ortqvist A et al (2006) Clonal and capsular types decide whether pneumococci will act as a primary or opportunistic pathogen. Clin Infect Dis 42:451–459PubMedGoogle Scholar
  129. 129.
    Smith AM, Botha RF, Koornhof HJ et al (2001) Emergence of a pneumococcal clone with cephalosporin resistance and penicillin susceptibility. Antimicrob Agents Chemother 45:26482650Google Scholar
  130. 130.
    Smith AM, Feldman C, Massidda O et al (2005) Altered PBP 2A and its role in the development of penicillin, cefotaxime, and ceftriaxone resistance in a clinical isolate of Streptococcus pneumoniae. Antimicrob Agents Chemother 49:2002–2007PubMedGoogle Scholar
  131. 131.
    Smith AM, Klugman KP (2001) Alterations in MurM, a cell wall muropeptide branching enzyme, increase high-level penicillin and cephalosporin resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother 45:2393–2396PubMedGoogle Scholar
  132. 132.
    Smith AM, Klugman KP (2003) Site-specific mutagenesis analysis of PBP 1A from a penicillin-cephalosporin-resistant pneumococcal isolate. Antimicrob Agents Chemother 48:387–389Google Scholar
  133. 133.
    Smith AM, Klugman KP (1995) Alterations in penicillin-binding protein 2B from penicillin-resistant wild-type strains of Streptococcus pneumoniae. Antimicrob Agents Chemother 39:859–867PubMedGoogle Scholar
  134. 134.
    Smith AM, Klugman KP (2005) Amino acid mutations essential to production of an altered PBP 2X conferring high-level β-lactam resistance in a clinical isolate of Streptococcus pneumoniae. Antimicrob Agents Chemother 49:4622–4627PubMedGoogle Scholar
  135. 135.
    Smith AM, Klugman KP (1998) Alterations in PBP1A essential for high-level penicillin resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother 42:1329–1333PubMedGoogle Scholar
  136. 136.
    Song JH, Yang JW, Jin JH et al (2000) Molecular characterization of multidrug-resistant Streptococcus pneumoniae isolates in Korea. The Asian Network for Surveillance of Resistant Pathogens (ANSORP) Study Group. J Clin Microbiol 38:1641–1644PubMedGoogle Scholar
  137. 137.
    Stingele F, Mollet B (1996) Disruption of the gene encoding penicillin-binding protein 2b (pbp2b) causes altered cell morphology and cease in exopolysaccharide production in Streptococcus thermophilus Sfi6. Mol Microbiol 22:357–366PubMedGoogle Scholar
  138. 138.
    Suzuki H, van Heijenoort Y, Tamura T et al (1980) In vitro peptidoglycan polymerization catalysed by penicillin-binding protein 1b of Escherichia coli K 12. FEBS Lett 110: 245–249PubMedGoogle Scholar
  139. 139.
    Throup JP, Koretke KK, Bryant AP et al (2000) A genomic analysis of two-component signal transduction in Streptococcus pneumoniae. Mol Microbiol 35:566–576PubMedGoogle Scholar
  140. 140.
    Trzcinski K, Thompson CM, Lipsitch M (2006) Single-step capsular transformation and acquisition of penicillin resistance in Streptococcus pneumoniae. J Bacteriol 186:3227–3452Google Scholar
  141. 141.
    van Heijenoort Y, Van Heijenoort J (1980) Biosynthesis of the peptidoglycan of Escherichia coli K 12. Properties of the in vitro polymerization by transglycosylation. FEBS Lett 110:241–244PubMedGoogle Scholar
  142. 142.
    Weber B, Ehlert K, Diehl A et al (2000) The fib locus in Streptococcus pneumoniae is required for peptidoglycan crosslinking and PBP-mediated β-lactam resistance. FEMS Microbiol Lett 188:81–85PubMedGoogle Scholar
  143. 143.
    Yamane A, Nakano H, Asahi Y et al (1996) Directly repeated insertion of 9-nucleotide sequence detected in penicillin-binding protein 2B gene of penicillin-resistant Streptococcus pneumoniae. Antimicrob Agents Chemother 40:1257–1259PubMedGoogle Scholar
  144. 144.
    Zähner D, Kaminski K, van der Linden M et al (2002) The ciaR/ciaH regulatory network of Streptococcus pneumoniae. J Mol Microbiol Biotechnol 4:211–216PubMedGoogle Scholar
  145. 145.
    Zapun A, Contreras-Martel C, Vernet T (2008) Penicillin-binding proteins and β-lactam resistance. FEMS Microbiol Rev 32:361–385PubMedGoogle Scholar
  146. 146.
    Zerfass I, Hakenbeck R, Denapaite D (2009) An important site in PBP2x of penicillin-resistant clinical isolates of Streptococcus pneumoniae: mutational analysis of Thr338. Antimicrob Agents Chemother 53:1107–1115PubMedGoogle Scholar
  147. 147.
    Zhao G, Meier TI, Hoskins J et al (2000) Identification and characterization of the penicillin-binding protein 2a of Streptococcus pneumoniae and its possible role in resistance to β-lactam antibiotics. Antimicrob Agents Chemother 44:1745–1748PubMedGoogle Scholar
  148. 148.
    Zighelboim S, Tomasz A (1980) Penicillin-binding proteins of multiply antibiotic-resistant South African strains of Streptococcus pneumoniae. Antimicrob Agents Chemother 17:434–442PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Regine Hakenbeck
    • 1
  • Dalia Denapaite
    • 1
  • Patrick Maurer
    • 1
  1. 1.Department of MicrobiologyUniversity of KaiserslauternKaiserslauternGermany

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