1887

Abstract

Lysins represent a novel class of anti-infectives derived from bacteriophage. Lysins are bacterial cell-wall hydrolytic enzymes that selectively and rapidly kill (≥3 log c.f.u. in 30 min) specific Gram-positive bacteria providing a targeted therapeutic approach with minimal impact on unrelated commensal flora. The potential for bacterial resistance to lysins is considered low due to targeting of highly conserved peptidoglycan components. Through cutting-edge genetic engineering, lysins can be assembled into large libraries of anti-infective agents tailored to any bacterium of interest including drug-resistant Gram-positive pathogens such as meticillin- and vancomycin-resistant , vancomycin-resistant and , and penicillin-resistant . Lysins can eliminate bacteria systemically and topically from mucosal surfaces and biofilms, as evidenced by experimental models of sepsis, endocarditis, pneumonia, meningitis, and nasopharyngeal, skin and vaginal decolonization. Furthermore, lysins can act synergistically with antibiotics and, in the process, resensitize bacteria to non-susceptible antibiotics. Clinical trials are being prepared to assess the safety and pharmacokinetic properties of lysins in humans.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.061028-0
2013-10-01
2019-10-23
Loading full text...

Full text loading...

/deliver/fulltext/jmm/62/10/1506.html?itemId=/content/journal/jmm/10.1099/jmm.0.061028-0&mimeType=html&fmt=ahah

References

  1. Becker S. C., Foster-Frey J., Donovan D. M.. ( 2008;). The phage K lytic enzyme LysK and lysostaphin act synergistically to kill MRSA. . FEMS Microbiol Lett 287:, 185–191. [CrossRef][PubMed]
    [Google Scholar]
  2. Briers Y., Volckaert G., Cornelissen A., Lagaert S., Michiels C. W., Hertveldt K., Lavigne R.. ( 2007;). Muralytic activity and modular structure of the endolysins of Pseudomonas aeruginosa bacteriophages phiKZ and EL. . Mol Microbiol 65:, 1334–1344. [CrossRef][PubMed]
    [Google Scholar]
  3. Briers Y., Walmagh M., Lavigne R.. ( 2011;). Use of bacteriophage endolysin EL188 and outer membrane permeabilizers against Pseudomonas aeruginosa. . J Appl Microbiol 110:, 778–785. [CrossRef][PubMed]
    [Google Scholar]
  4. Brüssow H., Hendrix R. W.. ( 2002;). Phage genomics. . Cell 108:, 13–16. [CrossRef][PubMed]
    [Google Scholar]
  5. Cheng Q., Fischetti V. A.. ( 2007;). Mutagenesis of a bacteriophage lytic enzyme PlyGBS significantly increases its antibacterial activity against group B streptococci. . Appl Microbiol Biotechnol 74:, 1284–1291. [CrossRef][PubMed]
    [Google Scholar]
  6. Cheng Q., Nelson D., Zhu S., Fischetti V. A.. ( 2005;). Removal of group B streptococci colonizing the vagina and oropharynx of mice with a bacteriophage lytic enzyme. . Antimicrob Agents Chemother 49:, 111–117. [CrossRef][PubMed]
    [Google Scholar]
  7. Daniel A., Euler C., Collin M., Chahales P., Gorelick K. J., Fischetti V. A.. ( 2010;). Synergism between a novel chimeric lysin and oxacillin protects against infection by methicillin-resistant Staphylococcus aureus.. Antimicrob Agents Chemother 54:, 1603–1612. [CrossRef][PubMed]
    [Google Scholar]
  8. Dhand A., Bayer A. S., Pogliano J., Yang S. J., Bolaris M., Nizet V., Wang G., Sakoulas G.. ( 2011;). Use of antistaphylococcal β-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: role of enhanced daptomycin binding. . Clin Infect Dis 53:, 158–163. [CrossRef][PubMed]
    [Google Scholar]
  9. Díaz E., López R., García J. L.. ( 1990;). Chimeric phage-bacterial enzymes: a clue to the modular evolution of genes. . Proc Natl Acad Sci U S A 87:, 8125–8129. [CrossRef][PubMed]
    [Google Scholar]
  10. Djurkovic S., Loeffler J. M., Fischetti V. A.. ( 2005;). Synergistic killing of Streptococcus pneumoniae with the bacteriophage lytic enzyme Cpl-1 and penicillin or gentamicin depends on the level of penicillin resistance. . Antimicrob Agents Chemother 49:, 1225–1228. [CrossRef][PubMed]
    [Google Scholar]
  11. Domenech M., García E., Moscoso M.. ( 2011;). In vitro destruction of Streptococcus pneumoniae biofilms with bacterial and phage peptidoglycan hydrolases. . Antimicrob Agents Chemother 55:, 4144–4148. [CrossRef][PubMed]
    [Google Scholar]
  12. Entenza J. M., Loeffler J. M., Grandgirard D., Fischetti V. A., Moreillon P.. ( 2005;). Therapeutic effects of bacteriophage Cpl-1 lysin against Streptococcus pneumoniae endocarditis in rats. . Antimicrob Agents Chemother 49:, 4789–4792. [CrossRef][PubMed]
    [Google Scholar]
  13. Eugster M. R., Loessner M. J.. ( 2012;). Wall teichoic acids restrict access of bacteriophage endolysin Ply118, Ply511, and PlyP40 cell wall binding domains to the Listeria monocytogenes peptidoglycan. . J Bacteriol 194:, 6498–6506. [CrossRef][PubMed]
    [Google Scholar]
  14. Eugster M. R., Haug M. C., Huwiler S. G., Loessner M. J.. ( 2011;). The cell wall binding domain of Listeria bacteriophage endolysin PlyP35 recognizes terminal GlcNAc residues in cell wall teichoic acid. . Mol Microbiol 81:, 1419–1432. [CrossRef][PubMed]
    [Google Scholar]
  15. Fenton M., Casey P. G., Hill C., Gahan C. G., Ross R. P., McAuliffe O., O’Mahony J., Maher F., Coffey A.. ( 2010a;). The truncated phage lysin CHAP(k) eliminates Staphylococcus aureus in the nares of mice. . Bioeng Bugs 1:, 404–407. [CrossRef][PubMed]
    [Google Scholar]
  16. Fenton M., Ross P., McAuliffe O., O’Mahony J., Coffey A.. ( 2010b;). Recombinant bacteriophage lysins as antibacterials. . Bioeng Bugs 1:, 9–16. [CrossRef][PubMed]
    [Google Scholar]
  17. Fernandes S., Proença D., Cantante C., Silva F. A., Leandro C., Lourenço S., Milheiriço C., de Lencastre H., Cavaco-Silva P.. & other authors ( 2012;). Novel chimerical endolysins with broad antimicrobial activity against methicillin-resistant Staphylococcus aureus. . Microb Drug Resist 18:, 333–343. [CrossRef][PubMed]
    [Google Scholar]
  18. Fischetti V. A.. ( 2003;). Novel method to control pathogenic bacteria on human mucous membranes. . Ann N Y Acad Sci 987:, 207–214. [CrossRef][PubMed]
    [Google Scholar]
  19. Fischetti V. A.. ( 2008;). Bacteriophage lysins as effective antibacterials. . Curr Opin Microbiol 11:, 393–400. [CrossRef][PubMed]
    [Google Scholar]
  20. Fischetti V. A., Nelson D., Schuch R.. ( 2006;). Reinventing phage therapy: are the parts greater than the sum?. Nat Biotechnol 24:, 1508–1511. [CrossRef][PubMed]
    [Google Scholar]
  21. Fowler V. G. Jr, Boucher H. W., Corey G. R., Abrutyn E., Karchmer A. W., Rupp M. E., Levine D. P., Chambers H. F., Tally F. P.. & other authors ( 2006;). Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus.. N Engl J Med 355:, 653–665. [CrossRef][PubMed]
    [Google Scholar]
  22. García P., Martínez B., Rodríguez L., Rodríguez A.. ( 2010;). Synergy between the phage endolysin LysH5 and nisin to kill Staphylococcus aureus in pasteurized milk. . Int J Food Microbiol 141:, 151–155. [CrossRef][PubMed]
    [Google Scholar]
  23. Grandgirard D., Loeffler J. M., Fischetti V. A., Leib S. L.. ( 2008;). Phage lytic enzyme Cpl-1 for antibacterial therapy in experimental pneumococcal meningitis. . J Infect Dis 197:, 1519–1522. [CrossRef][PubMed]
    [Google Scholar]
  24. Gravitz L.. ( 2012;). Turning a new phage. . Nat Med 18:, 1318–1320. [CrossRef][PubMed]
    [Google Scholar]
  25. Horgan M., O’Flynn G., Garry J., Cooney J., Coffey A., Fitzgerald G. F., Ross R. P., McAuliffe O.. ( 2009;). Phage lysin LysK can be truncated to its CHAP domain and retain lytic activity against live antibiotic-resistant staphylococci. . Appl Environ Microbiol 75:, 872–874. [CrossRef][PubMed]
    [Google Scholar]
  26. Ince J., McNally A.. ( 2009;). Development of rapid, automated diagnostics for infectious disease: advances and challenges. . Expert Rev Med Devices 6:, 641–651. [CrossRef][PubMed]
    [Google Scholar]
  27. Jado I., López R., García E., Fenoll A., Casal J., García P..Spanish Pneumococcal Infection Study Network ( 2003;). Phage lytic enzymes as therapy for antibiotic-resistant Streptococcus pneumoniae infection in a murine sepsis model. . J Antimicrob Chemother 52:, 967–973. [CrossRef][PubMed]
    [Google Scholar]
  28. Kokai-Kun J. F., Chanturiya T., Mond J. J.. ( 2009;). Lysostaphin eradicates established Staphylococcus aureus biofilms in jugular vein catheterized mice. . J Antimicrob Chemother 64:, 94–100. [CrossRef][PubMed]
    [Google Scholar]
  29. Labrie S. J., Samson J. E., Moineau S.. ( 2010;). Bacteriophage resistance mechanisms. . Nat Rev Microbiol 8:, 317–327. [CrossRef][PubMed]
    [Google Scholar]
  30. Lai M. J., Lin N. T., Hu A., Soo P. C., Chen L. K., Chen L. H., Chang K. C.. ( 2011;). Antibacterial activity of Acinetobacter baumannii phage φAB2 endolysin (LysAB2) against both gram-positive and gram-negative bacteria. . Appl Microbiol Biotechnol 90:, 529–539. [CrossRef][PubMed]
    [Google Scholar]
  31. Loeffler J. M., Fischetti V. A.. ( 2003;). Synergistic lethal effect of a combination of phage lytic enzymes with different activities on penicillin-sensitive and -resistant Streptococcus pneumoniae strains. . Antimicrob Agents Chemother 47:, 375–377. [CrossRef][PubMed]
    [Google Scholar]
  32. Loeffler J. M., Nelson D., Fischetti V. A.. ( 2001;). Rapid killing of Streptococcus pneumoniae with a bacteriophage cell wall hydrolase. . Science 294:, 2170–2172. [CrossRef][PubMed]
    [Google Scholar]
  33. Loeffler J. M., Djurkovic S., Fischetti V. A.. ( 2003;). Phage lytic enzyme Cpl-1 as a novel antimicrobial for pneumococcal bacteremia. . Infect Immun 71:, 6199–6204. [CrossRef][PubMed]
    [Google Scholar]
  34. Loessner M. J., Kramer K., Ebel F., Scherer S.. ( 2002;). C-terminal domains of Listeria monocytogenes bacteriophage murein hydrolases determine specific recognition and high-affinity binding to bacterial cell wall carbohydrates. . Mol Microbiol 44:, 335–349. [CrossRef][PubMed]
    [Google Scholar]
  35. Lukacik P., Barnard T. J., Keller P. W., Chaturvedi K. S., Seddiki N., Fairman J. W., Noinaj N., Kirby T. L., Henderson J. P.. & other authors ( 2012;). Structural engineering of a phage lysin that targets Gram-negative pathogens. . Proc Natl Acad Sci U S A 109:, 9857–9862. [CrossRef][PubMed]
    [Google Scholar]
  36. Mao J., Schmelcher M., Harty W. J., Foster-Frey J., Donovan D. M.. ( 2013;). Chimeric Ply187 endolysin kills Staphylococcus aureus more effectively than the parental enzyme. . FEMS Microbiol Lett 342:, 30–36. [CrossRef][PubMed]
    [Google Scholar]
  37. Marconescu P., Graviss E. A., Musher D. M.. ( 2012;). Rates of killing of methicillin-resistant Staphylococcus aureus by ceftaroline, daptomycin, and telavancin compared to that of vancomycin. . Scand J Infect Dis 44:, 620–622. [CrossRef][PubMed]
    [Google Scholar]
  38. Mayer M. J., Narbad A., Gasson M. J.. ( 2008;). Molecular characterization of a Clostridium difficile bacteriophage and its cloned biologically active endolysin. . J Bacteriol 190:, 6734–6740. [CrossRef][PubMed]
    [Google Scholar]
  39. McCullers J. A., Karlström A., Iverson A. R., Loeffler J. M., Fischetti V. A.. ( 2007;). Novel strategy to prevent otitis media caused by colonizing Streptococcus pneumoniae. . PLoS Pathog 3:, e28. [CrossRef][PubMed]
    [Google Scholar]
  40. Morita M., Tanji Y., Orito Y., Mizoguchi K., Soejima A., Unno H.. ( 2001;). Functional analysis of antibacterial activity of Bacillus amyloliquefaciens phage endolysin against Gram-negative bacteria. . FEBS Lett 500:, 56–59. [CrossRef][PubMed]
    [Google Scholar]
  41. Navarre W. W., Ton-That H., Faull K. F., Schneewind O.. ( 1999;). Multiple enzymatic activities of the murein hydrolase from staphylococcal phage φ11. Identification of a d-alanyl-glycine endopeptidase activity. . J Biol Chem 274:, 15847–15856. [CrossRef][PubMed]
    [Google Scholar]
  42. Nelson D., Loomis L., Fischetti V. A.. ( 2001;). Prevention and elimination of upper respiratory colonization of mice by group A streptococci by using a bacteriophage lytic enzyme. . Proc Natl Acad Sci U S A 98:, 4107–4112. [CrossRef][PubMed]
    [Google Scholar]
  43. Nelson D. C., Schmelcher M., Rodriguez-Rubio L., Klumpp J., Pritchard D. G., Dong S., Donovan D. M.. ( 2012;). Endolysins as antimicrobials. . Adv Virus Res 83:, 299–365. [CrossRef][PubMed]
    [Google Scholar]
  44. Orito Y., Morita M., Hori K., Unno H., Tanji Y.. ( 2004;). Bacillus amyloliquefaciens phage endolysin can enhance permeability of Pseudomonas aeruginosa outer membrane and induce cell lysis. . Appl Microbiol Biotechnol 65:, 105–109. [CrossRef][PubMed]
    [Google Scholar]
  45. Pastagia M., Euler C., Chahales P., Fuentes-Duculan J., Krueger J. G., Fischetti V. A.. ( 2011;). A novel chimeric lysin shows superiority to mupirocin for skin decolonization of methicillin-resistant and -sensitive Staphylococcus aureus strains. . Antimicrob Agents Chemother 55:, 738–744. [CrossRef][PubMed]
    [Google Scholar]
  46. Rashel M., Uchiyama J., Ujihara T., Uehara Y., Kuramoto S., Sugihara S., Yagyu K., Muraoka A., Sugai M.. & other authors ( 2007;). Efficient elimination of multidrug-resistant Staphylococcus aureus by cloned lysin derived from bacteriophage φMR11. . J Infect Dis 196:, 1237–1247. [CrossRef][PubMed]
    [Google Scholar]
  47. Resch G., Moreillon P., Fischetti V. A.. ( 2011;). A stable phage lysin (Cpl-1) dimer with increased antipneumococcal activity and decreased plasma clearance. . Int J Antimicrob Agents 38:, 516–521. [CrossRef][PubMed]
    [Google Scholar]
  48. Reyes A., Haynes M., Hanson N., Angly F. E., Heath A. C., Rohwer F., Gordon J. I.. ( 2010;). Viruses in the faecal microbiota of monozygotic twins and their mothers. . Nature 466:, 334–338. [CrossRef][PubMed]
    [Google Scholar]
  49. Rodríguez-Rubio L., Martínez B., Rodríguez A., Donovan D. M., García P.. ( 2012;). Enhanced staphylolytic activity of the Staphylococcus aureus bacteriophage vB_SauS-phiIPLA88 HydH5 virion-associated peptidoglycan hydrolase: fusions, deletions, and synergy with LysH5. . Appl Environ Microbiol 78:, 2241–2248. [CrossRef][PubMed]
    [Google Scholar]
  50. Sass P., Bierbaum G.. ( 2007;). Lytic activity of recombinant bacteriophage φ11 and φ12 endolysins on whole cells and biofilms of Staphylococcus aureus. . Appl Environ Microbiol 73:, 347–352. [CrossRef][PubMed]
    [Google Scholar]
  51. Schmelcher M., Shabarova T., Eugster M. R., Eichenseher F., Tchang V. S., Banz M., Loessner M. J.. ( 2010;). Rapid multiplex detection and differentiation of Listeria cells by use of fluorescent phage endolysin cell wall binding domains. . Appl Environ Microbiol 76:, 5745–5756. [CrossRef][PubMed]
    [Google Scholar]
  52. Schmelcher M., Tchang V. S., Loessner M. J.. ( 2011;). Domain shuffling and module engineering of Listeria phage endolysins for enhanced lytic activity and binding affinity. . Microb Biotechnol 4:, 651–662. [CrossRef][PubMed]
    [Google Scholar]
  53. Schmitz J. E., Ossiprandi M. C., Rumah K. R., Fischetti V. A.. ( 2011;). Lytic enzyme discovery through multigenomic sequence analysis in Clostridium perfringens. . Appl Microbiol Biotechnol 89:, 1783–1795. [CrossRef][PubMed]
    [Google Scholar]
  54. Schuch R., Nelson D., Fischetti V. A.. ( 2002;). A bacteriolytic agent that detects and kills Bacillus anthracis. . Nature 418:, 884–889. [CrossRef][PubMed]
    [Google Scholar]
  55. Schuch R., Fischetti V. A., Nelson D. C.. ( 2009;). A genetic screen to identify bacteriophage lysins. . Methods Mol Biol 502:, 307–319. [CrossRef][PubMed]
    [Google Scholar]
  56. Schuch R., Pelzek A. J., Raz A., Euler C. W., Ryan P. A., Winer B. Y., Farnsworth A., Bhaskaran S. S., Stebbins C. E.. & other authors ( 2013;). Use of a bacteriophage lysin to identify a novel target for antimicrobial development. . PLoS ONE 8:, e60754. [CrossRef][PubMed]
    [Google Scholar]
  57. Shen Y., Köller T., Kreikemeyer B., Nelson D. C.. ( 2013;). Rapid degradation of Streptococcus pyogenes biofilms by PlyC, a bacteriophage-encoded endolysin. . J Antimicrob Chemother 68:, 1818–1824. [CrossRef][PubMed]
    [Google Scholar]
  58. Thurber R. V.. ( 2009;). Current insights into phage biodiversity and biogeography. . Curr Opin Microbiol 12:, 582–587. [CrossRef][PubMed]
    [Google Scholar]
  59. Velloso L. M., Bhaskaran S. S., Schuch R., Fischetti V. A., Stebbins C. E.. ( 2008;). A structural basis for the allosteric regulation of non-hydrolysing UDP-GlcNAc 2-epimerases. . EMBO Rep 9:, 199–205. [CrossRef][PubMed]
    [Google Scholar]
  60. Wang I. N., Smith D. L., Young R.. ( 2000;). Holins: the protein clocks of bacteriophage infections. . Annu Rev Microbiol 54:, 799–825. [CrossRef][PubMed]
    [Google Scholar]
  61. Witzenrath M., Schmeck B., Doehn J. M., Tschernig T., Zahlten J., Loeffler J. M., Zemlin M., Müller H., Gutbier B.. & other authors ( 2009;). Systemic use of the endolysin Cpl-1 rescues mice with fatal pneumococcal pneumonia. . Crit Care Med 37:, 642–649. [CrossRef][PubMed]
    [Google Scholar]
  62. Yang H., Wang D. B., Dong Q., Zhang Z., Cui Z., Deng J., Yu J., Zhang X. E., Wei H.. ( 2012;). Existence of separate domains in lysin PlyG for recognizing Bacillus anthracis spores and vegetative cells. . Antimicrob Agents Chemother 56:, 5031–5039. [CrossRef][PubMed]
    [Google Scholar]
  63. Yoong P., Schuch R., Nelson D., Fischetti V. A.. ( 2004;). Identification of a broadly active phage lytic enzyme with lethal activity against antibiotic-resistant Enterococcus faecalis and Enterococcus faecium. . J Bacteriol 186:, 4808–4812. [CrossRef][PubMed]
    [Google Scholar]
  64. Yother J., Leopold K., White J., Fischer W.. ( 1998;). Generation and properties of a Streptococcus pneumoniae mutant which does not require choline or analogs for growth. . J Bacteriol 180:, 2093–2101.[PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.061028-0
Loading
/content/journal/jmm/10.1099/jmm.0.061028-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error