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. 1997 May;179(10):3342–3349. doi: 10.1128/jb.179.10.3342-3349.1997

A novel resistance mechanism against beta-lactams in Streptococcus pneumoniae involves CpoA, a putative glycosyltransferase.

T Grebe 1, J Paik 1, R Hakenbeck 1
PMCID: PMC179116  PMID: 9150233

Abstract

Piperacillin resistance in Streptococcus pneumoniae was mediated by mutations in a novel gene, cpoA, that also confer transformation deficiency and a decrease in penicillin-binding protein la. cpoA is part of an operon located downstream of the primary sigma factor of S. pneumoniae. The deduced protein, CpoA, and the peptide encoded by the adjacent 3' open reading frame contained domains homologous to glycosyltransferases of procaryotes and eucaryotes that act on membrane-associated substrates, such as enzymes functioning in lipopolysaccharide core biosynthesis of gram-negative bacteria, RodD of Bacillus subtilis, which is involved in teichoic acid biosynthesis, and the human PIG-A protein, which is required for early steps of glycosylphosphatidylinositol anchor biosynthesis. This suggests that the cpo operon has a similar function related to cell surface components.

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Selected References

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  1. Altschul S. F., Gish W., Miller W., Myers E. W., Lipman D. J. Basic local alignment search tool. J Mol Biol. 1990 Oct 5;215(3):403–410. doi: 10.1016/S0022-2836(05)80360-2. [DOI] [PubMed] [Google Scholar]
  2. Blake M. S., Johnston K. H., Russell-Jones G. J., Gotschlich E. C. A rapid, sensitive method for detection of alkaline phosphatase-conjugated anti-antibody on Western blots. Anal Biochem. 1984 Jan;136(1):175–179. doi: 10.1016/0003-2697(84)90320-8. [DOI] [PubMed] [Google Scholar]
  3. Chen J. D., Morrison D. A. Construction and properties of a new insertion vector, pJDC9, that is protected by transcriptional terminators and useful for cloning of DNA from Streptococcus pneumoniae. Gene. 1988 Apr 15;64(1):155–164. doi: 10.1016/0378-1119(88)90489-1. [DOI] [PubMed] [Google Scholar]
  4. Colman G. The application of computers to the classification of streptococci. J Gen Microbiol. 1968 Jan;50(1):149–158. doi: 10.1099/00221287-50-1-149. [DOI] [PubMed] [Google Scholar]
  5. Devereux J., Haeberli P., Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. doi: 10.1093/nar/12.1part1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fassler J. S., Gray W., Lee J. P., Yu G. Y., Gingerich G. The Saccharomyces cerevisiae SPT14 gene is essential for normal expression of the yeast transposon, Ty, as well as for expression of the HIS4 gene and several genes in the mating pathway. Mol Gen Genet. 1991 Nov;230(1-2):310–320. doi: 10.1007/BF00290682. [DOI] [PubMed] [Google Scholar]
  7. Grebe T., Hakenbeck R. Penicillin-binding proteins 2b and 2x of Streptococcus pneumoniae are primary resistance determinants for different classes of beta-lactam antibiotics. Antimicrob Agents Chemother. 1996 Apr;40(4):829–834. doi: 10.1128/aac.40.4.829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Guenzi E., Gasc A. M., Sicard M. A., Hakenbeck R. A two-component signal-transducing system is involved in competence and penicillin susceptibility in laboratory mutants of Streptococcus pneumoniae. Mol Microbiol. 1994 May;12(3):505–515. doi: 10.1111/j.1365-2958.1994.tb01038.x. [DOI] [PubMed] [Google Scholar]
  9. Hakenbeck R., Ellerbrok H., Briese T., Handwerger S., Tomasz A. Penicillin-binding proteins of penicillin-susceptible and -resistant pneumococci: immunological relatedness of altered proteins and changes in peptides carrying the beta-lactam binding site. Antimicrob Agents Chemother. 1986 Oct;30(4):553–558. doi: 10.1128/aac.30.4.553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hakenbeck R., Grebe T., Guenzi E., König A., Krauss J., Reichmann P. The role of penicillin-binding proteins in penicillin resistance of Streptococcus pneumoniae. Dev Biol Stand. 1995;85:115–123. [PubMed] [Google Scholar]
  11. Hakenbeck R., Martin C., Dowson C., Grebe T. Penicillin-binding protein 2b of Streptococcus pneumoniae in piperacillin-resistant laboratory mutants. J Bacteriol. 1994 Sep;176(17):5574–5577. doi: 10.1128/jb.176.17.5574-5577.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hakenbeck R. Target-mediated resistance to beta-lactam antibiotics. Biochem Pharmacol. 1995 Oct 12;50(8):1121–1127. doi: 10.1016/0006-2952(95)00158-v. [DOI] [PubMed] [Google Scholar]
  13. Hakenbeck R., Tornette S., Adkinson N. F. Interaction of non-lytic beta-lactams with penicillin-binding proteins in Streptococcus pneumoniae. J Gen Microbiol. 1987 Mar;133(3):755–760. doi: 10.1099/00221287-133-3-755. [DOI] [PubMed] [Google Scholar]
  14. Hakenbeck R., Waks S., Tomasz A. Characterization of cell wall polymers secreted into the growth medium of lysis-defective pneumococci during treatment with penicillin and other inhibitors of cell wall synthesis. Antimicrob Agents Chemother. 1978 Feb;13(2):302–311. doi: 10.1128/aac.13.2.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Honeyman A. L., Stewart G. C. The nucleotide sequence of the rodC operon of Bacillus subtilis. Mol Microbiol. 1989 Sep;3(9):1257–1268. doi: 10.1111/j.1365-2958.1989.tb00276.x. [DOI] [PubMed] [Google Scholar]
  16. Hui F. M., Morrison D. A. Genetic transformation in Streptococcus pneumoniae: nucleotide sequence analysis shows comA, a gene required for competence induction, to be a member of the bacterial ATP-dependent transport protein family. J Bacteriol. 1991 Jan;173(1):372–381. doi: 10.1128/jb.173.1.372-381.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Håvarstein L. S., Coomaraswamy G., Morrison D. A. An unmodified heptadecapeptide pheromone induces competence for genetic transformation in Streptococcus pneumoniae. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11140–11144. doi: 10.1073/pnas.92.24.11140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Håvarstein L. S., Holo H., Nes I. F. The leader peptide of colicin V shares consensus sequences with leader peptides that are common among peptide bacteriocins produced by gram-positive bacteria. Microbiology. 1994 Sep;140(Pt 9):2383–2389. doi: 10.1099/13500872-140-9-2383. [DOI] [PubMed] [Google Scholar]
  19. Johnston T. C., Thompson R. B., Baldwin T. O. Nucleotide sequence of the luxB gene of Vibrio harveyi and the complete amino acid sequence of the beta subunit of bacterial luciferase. J Biol Chem. 1986 Apr 15;261(11):4805–4811. [PubMed] [Google Scholar]
  20. Krauss J., van der Linden M., Grebe T., Hakenbeck R. Penicillin-binding proteins 2x and 2b as primary PBP targets in Streptococcus pneumoniae. Microb Drug Resist. 1996 Summer;2(2):183–186. doi: 10.1089/mdr.1996.2.183. [DOI] [PubMed] [Google Scholar]
  21. LACKS S., HOTCHKISS R. D. A study of the genetic material determining an enzyme in Pneumococcus. Biochim Biophys Acta. 1960 Apr 22;39:508–518. doi: 10.1016/0006-3002(60)90205-5. [DOI] [PubMed] [Google Scholar]
  22. Laible G., Hakenbeck R. Five independent combinations of mutations can result in low-affinity penicillin-binding protein 2x of Streptococcus pneumoniae. J Bacteriol. 1991 Nov;173(21):6986–6990. doi: 10.1128/jb.173.21.6986-6990.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Laible G., Hakenbeck R. Penicillin-binding proteins in beta-lactam-resistant laboratory mutants of Streptococcus pneumoniae. Mol Microbiol. 1987 Nov;1(3):355–363. doi: 10.1111/j.1365-2958.1987.tb01942.x. [DOI] [PubMed] [Google Scholar]
  24. Laible G., Hakenbeck R., Sicard M. A., Joris B., Ghuysen J. M. Nucleotide sequences of the pbpX genes encoding the penicillin-binding proteins 2x from Streptococcus pneumoniae R6 and a cefotaxime-resistant mutant, C506. Mol Microbiol. 1989 Oct;3(10):1337–1348. doi: 10.1111/j.1365-2958.1989.tb00115.x. [DOI] [PubMed] [Google Scholar]
  25. Lazarevic V., Karamata D. The tagGH operon of Bacillus subtilis 168 encodes a two-component ABC transporter involved in the metabolism of two wall teichoic acids. Mol Microbiol. 1995 Apr;16(2):345–355. doi: 10.1111/j.1365-2958.1995.tb02306.x. [DOI] [PubMed] [Google Scholar]
  26. Livermore D. M. beta-Lactamases in laboratory and clinical resistance. Clin Microbiol Rev. 1995 Oct;8(4):557–584. doi: 10.1128/cmr.8.4.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lonetto M. A., Brown K. L., Rudd K. E., Buttner M. J. Analysis of the Streptomyces coelicolor sigE gene reveals the existence of a subfamily of eubacterial RNA polymerase sigma factors involved in the regulation of extracytoplasmic functions. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7573–7577. doi: 10.1073/pnas.91.16.7573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Maina C. V., Riggs P. D., Grandea A. G., 3rd, Slatko B. E., Moran L. S., Tagliamonte J. A., McReynolds L. A., Guan C. D. An Escherichia coli vector to express and purify foreign proteins by fusion to and separation from maltose-binding protein. Gene. 1988 Dec 30;74(2):365–373. doi: 10.1016/0378-1119(88)90170-9. [DOI] [PubMed] [Google Scholar]
  29. Martin B., García P., Castanié M. P., Claverys J. P. The recA gene of Streptococcus pneumoniae is part of a competence-induced operon and controls lysogenic induction. Mol Microbiol. 1995 Jan;15(2):367–379. doi: 10.1111/j.1365-2958.1995.tb02250.x. [DOI] [PubMed] [Google Scholar]
  30. Martin C., Briese T., Hakenbeck R. Nucleotide sequences of genes encoding penicillin-binding proteins from Streptococcus pneumoniae and Streptococcus oralis with high homology to Escherichia coli penicillin-binding proteins 1a and 1b. J Bacteriol. 1992 Jul;174(13):4517–4523. doi: 10.1128/jb.174.13.4517-4523.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Martinez E., Bartolomé B., de la Cruz F. pACYC184-derived cloning vectors containing the multiple cloning site and lacZ alpha reporter gene of pUC8/9 and pUC18/19 plasmids. Gene. 1988 Aug 15;68(1):159–162. doi: 10.1016/0378-1119(88)90608-7. [DOI] [PubMed] [Google Scholar]
  32. Messing J., Crea R., Seeburg P. H. A system for shotgun DNA sequencing. Nucleic Acids Res. 1981 Jan 24;9(2):309–321. doi: 10.1093/nar/9.2.309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Miyata T., Takeda J., Iida Y., Yamada N., Inoue N., Takahashi M., Maeda K., Kitani T., Kinoshita T. The cloning of PIG-A, a component in the early step of GPI-anchor biosynthesis. Science. 1993 Feb 26;259(5099):1318–1320. doi: 10.1126/science.7680492. [DOI] [PubMed] [Google Scholar]
  34. Nikaido H. Outer membrane barrier as a mechanism of antimicrobial resistance. Antimicrob Agents Chemother. 1989 Nov;33(11):1831–1836. doi: 10.1128/aac.33.11.1831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Parkinson J. S., Kofoid E. C. Communication modules in bacterial signaling proteins. Annu Rev Genet. 1992;26:71–112. doi: 10.1146/annurev.ge.26.120192.000443. [DOI] [PubMed] [Google Scholar]
  36. Popham D. L., Setlow P. Cloning, nucleotide sequence, and mutagenesis of the Bacillus subtilis ponA operon, which codes for penicillin-binding protein (PBP) 1 and a PBP-related factor. J Bacteriol. 1995 Jan;177(2):326–335. doi: 10.1128/jb.177.2.326-335.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Puyet A., Espinosa M. Structure of the maltodextrin-uptake locus of Streptococcus pneumoniae. Correlation to the Escherichia coli maltose regulon. J Mol Biol. 1993 Apr 5;230(3):800–811. doi: 10.1006/jmbi.1993.1202. [DOI] [PubMed] [Google Scholar]
  38. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schönbächler M., Horvath A., Fassler J., Riezman H. The yeast spt14 gene is homologous to the human PIG-A gene and is required for GPI anchor synthesis. EMBO J. 1995 Apr 18;14(8):1637–1645. doi: 10.1002/j.1460-2075.1995.tb07152.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sibold C., Henrichsen J., König A., Martin C., Chalkley L., Hakenbeck R. Mosaic pbpX genes of major clones of penicillin-resistant Streptococcus pneumoniae have evolved from pbpX genes of a penicillin-sensitive Streptococcus oralis. Mol Microbiol. 1994 Jun;12(6):1013–1023. doi: 10.1111/j.1365-2958.1994.tb01089.x. [DOI] [PubMed] [Google Scholar]
  41. Tiraby J. G., Fox M. S. Marker discrimination and mutagen-induced alterations in pneumococcal transformation. Genetics. 1974 Jul;77(3):449–458. doi: 10.1093/genetics/77.3.449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tomasz A., Mosser J. L. On the nature of the pneumococcal activator substance. Proc Natl Acad Sci U S A. 1966 Jan;55(1):58–66. doi: 10.1073/pnas.55.1.58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Waks S., Tomasz A. Secretion of cell wall polymers into the growth medium of lysis-defective pneumococci during treatment with penicillin and other inhibitors of cell wall synthesis. Antimicrob Agents Chemother. 1978 Feb;13(2):293–301. doi: 10.1128/aac.13.2.293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Williamson R., Hakenbeck R., Tomasz A. In vivo interaction of beta-lactam antibiotics with the penicillin-binding proteins of Streptococcus pneumoniae. Antimicrob Agents Chemother. 1980 Oct;18(4):629–637. doi: 10.1128/aac.18.4.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zähner D., Grebe T., Guenzi E., Krauss J., van der Linden M., Terhune K., Stock J. B., Hakenbeck R. Resistance determinants for beta-lactam antibiotics in laboratory mutants of Streptococcus pneumoniae that are involved in genetic competence. Microb Drug Resist. 1996 Summer;2(2):187–191. doi: 10.1089/mdr.1996.2.187. [DOI] [PubMed] [Google Scholar]

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