Endolysins

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Endolysins (also murein hydrolases ) are hydrolytic enzymes encoded by bacteriophages (phages for short) and produced by bacteria during an infection . They are produced in the last phase of the lytic cycle in order to cut the cell wall of the bacterial host at specific points and thus ensure the release of the phage progeny. Endolysins are highly specialized enzymes that dissolve the cell walls of Gram-positive bacteria and therefore act as bacteriocins . Endolysins hydrolyze the murein in the peptidoglycan layer of bacterial cell walls, which is why they are discussed as a possible alternative to the therapy of antibiotic- resistant bacteria. So far there is only one enzyme approved as a medical product (the endolysin Staphefekt is used in creams and gels ), but no corresponding drug approvals.

properties

Lytic bacteriophages have developed as specific bacterial viruses in the course of evolution together with their hosts and have repeatedly adapted. Endolysins have thus also been optimized in their mode of action over millions of years and - like their phages - have a corresponding host specificity. If they cannot develop their effect because they do not recognize the surface structures of the bacterium and cannot find the right connections in the bacterial shell, they have no effect.

Phage endolysins against Gram-positive bacteria have a modular structure, with the catalytically active protein domains being spatially separated from the areas responsible for recognizing the bacterial surface molecules. The cell wall binding domain (CBD) ensures recognition and binding to a cell wall . The enzymatically active domains (EAD) can be amidases , endopeptidases , glucosaminidases, muramidases , and the like. a. The different enzyme classes only cleave very specific compounds within the bacterial peptidoglycan envelope that are typical for their respective host . The endolysins each split a highly conserved compound specific to the respective bacterial species in the peptidoglycan envelope, so that it is irreparably damaged. The perforated bacterial shell can no longer withstand the high internal osmotic pressure , and the bacterium bursts , releasing the newly formed bacteriophages. This lytic effect from outside ('exolytic') cannot be exerted directly by endolysins in Gram-negative bacteria, since in these an outer membrane prevents access to the peptidoglycan envelope.

effectiveness

Due to the coevolution of bacteria and bacteriophages, phage lysins are usually species-specific or even strain-specific. They can therefore only act against those types of bacteria or bacterial strains for which the particular phage from which they were isolated was specific. The formation of resistance to phage endolysins on the part of the bacteria is regarded as an extremely unlikely event and has not yet been proven in laboratory experiments. In contrast to antibiotics, which penetrate the bacteria and intervene in the metabolism in different ways , externally administered endolysins have an immediate effect, so that bacteria have less chance of adapting.

Side effects

Unlike antibiotics, due to their limited spectrum of activity, they have no effect on other types of bacteria, nor on plant, animal or human cells. An allergic reaction in sensitive people cannot be completely ruled out, as endolysins are proteins .

Applications

Endolysins are being investigated for use against Gram-positive bacteria on mucous membranes , for systemic infection, in diagnostics, to ward off bioterrorism, to eliminate food pathogens and to reduce plant damage in agriculture. As bacterial proteins, they can only be used topically in humans , since an immune response is induced in the body against foreign proteins , which either leads to the premature breakdown of the endolysins or to undesirable inflammatory reactions against endolysins.

The proprietary endolysin Staphefekt SA.100 has three functional portions having different functions, and together provide a narrow host specificity: a CBD for recognition and binding to the surface molecules of Staphylococcus aureus and two enzymatically active domains, an endopeptidase and an amidase. It works almost exclusively against bacteria of the Staphylococcus aureus species and is used in Gladskin creams and gels from the Dutch company Micreos Human Health to relieve the symptoms of skin diseases such as acne , rosacea , eczema and skin irritation.

Synthetic endolysins

Synthetic endolysins are artificially produced modified antimicrobial proteins from the group of endolysins. Synthetic endolysins dock nonspecifically to the bacterial cell wall via charge differences and lead to a breakdown of the peptidoglycan of the bacteria . The bacteria lyse due to the osmotic pressure inside . Various synthetic endolysins have been described, some under the brand name Artilysins . Artilysins are fusion proteins of a cell-penetrating peptide and an endolysin and act on both pathogenic Gram-negative and Gram-positive bacteria. Synthetic endolysins have no effect on the metabolism within the cell and therefore do not require an active metabolism by the bacteria, so cells with a resting metabolism are also eliminated. Persistent cells play an important role in chronic diseases. Due to their mode of action, resistance stability and specificity, as well as a lack of cytotoxicity , synthetic endolysins represent an alternative to conventional antimicrobial substances.

literature

  • Lauren Gravitz: Turning a new phage . In: Nature Medicine . tape 18 , no. 9 , September 2012, p. 1318-1320 , doi : 10.1038 / nm0912-1318 .

Individual evidence

  1. ↑ a b M. Fenton, P. Ross, O. McAuliffe, J. O'Mahony, A. Coffey: Recombinant bacteriophage lysins as antibacterials. In: Bioengineered bugs. Volume 1, number 1, 2010, pp. 9-16, doi: 10.4161 / bbug.1.1.9818 , PMID 21327123 , PMC 3035150 (free full text).
  2. ^ Mathias Schmelcher, David M. Donovan, Martin J. Loessner: Bacteriophage endolysins as novel antimicrobials . In: Future Microbiology . tape 7 , no. 10 , October 2012, p. 1147–1171 , doi : 10.2217 / fmb.12.97 .
  3. ^ E. García, JL García, P. García, A. Arrarás, JM Sánchez-Puelles, R. López: Molecular Evolution of Lytic Enzymes of Streptococcus pneumoniae and its Bacteriophages . In: PNAS 85, No. 3, 1988, pp. 914-918, doi: 10.1073 / pnas.85.3.914 , PMID 3422470 , PMC 279667 (free full text).
  4. ↑ DC Nelson, M. Schmelcher, L. Rodriguez-Rubio, J. Klumpp, DG Pritchard, S. Dong, DM Donovan: Endolysins as antimicrobials. In: Advances in virus research. Volume 83, 2012, pp. 299-365, doi: 10.1016 / B978-0-12-394438-2.00007-4 , PMID 22748813 .
  5. ↑ Martin J. Loessner: Bacteriophage endolysins - current state of research and applications . In: Current Opinion in Microbiology . tape 8 , no. 4 , August 2005, p. 480-487 , doi : 10.1016 / j.mib.2005.06.002 .
  6. ^ A b Vincent A. Fischetti: Bacteriophage endolysins: A novel anti-infective to control Gram-positive pathogens . In: International Journal of Medical Microbiology . tape 300 , no. 6 , August 2010, p. 357-362 , doi : 10.1016 / j.ijmm.2010.04.002 , PMID 20452280 , PMC 3666336 (free full text).
  7. ↑ Lorena Rodríguez-Rubio, Beatriz Martínez, Ana Rodríguez, David M. Donovan, Friedrich Götz, Pilar García: The Phage Lytic Proteins from the Staphylococcus aureus Bacteriophage vB_SauS-phiIPLA88 Display Multiple Active Catalytic Domains and Dooccal Not Trigger Staphy . In: PLoS ONE . tape 8 , no. 5 , May 28, 2013, p. e64671 , doi : 10.1371 / journal.pone.0064671 .
  8. ↑ AC Fluit, S. van Marm, F. Eichenseher, MJ Loessner, F. Pietersma, ECH Boel: Killing And Lysis Of Staphylococcus aureus And Other Staphylococci By An Engineered Endolysin . In: ICAAC . F-1516, 2012 ( abstract [accessed September 20, 2013] poster).
  9. ↑ ABDA database, accessed on December 28, 2016.
  10. ↑ H. Yang, J. Yu, H. Wei: Engineered bacteriophage lysins as novel anti-infectives. In: Frontiers in Microbiology. Volume 5, 2014, p. 542, doi: 10.3389 / fmicb.2014.00542 , PMID 25360133 , PMC 4199284 (free full text).
  11. ^ Y. Briers, R. Lavigne: Breaking barriers: expansion of the use of endolysins as novel antibacterials against Gram-negative bacteria. In: Future microbiology. Volume 10, number 3, 2015, pp. 377-390, doi: 10.2217 / fmb.15.8 , PMID 25812461 .
  12. ↑ E. Schirmeier, P. Zimmermann, V. Hofmann, M. Biebl, H. Gerstmans, VE Maervoet, Y. Briers: Inhibitory and bactericidal effect of Artilysin Art-175 against colistin-resistant mcr-1-positive Escherichia coli isolates. In: International journal of antimicrobial agents. Volume 51, number 3, 03 2018, pp. 528-529, doi: 10.1016 / j.ijantimicag.2017.08.027 , PMID 28843823 .
  13. ↑ L. Rodríguez-Rubio, WL Chang, D. Gutiérrez, R. Lavigne, B. Martínez, A. Rodríguez, SK Govers, A. Aertsen, C. Hirl, M. Biebl, Y. Briers, P. García: ' Artilysation of endolysin λSa2lys strongly improves its enzymatic and antibacterial activity against streptococci. In: Scientific Reports . Volume 6, 10 2016, p. 35382, doi: 10.1038 / srep35382 , PMID 27775093 , PMC 5075790 (free full text).
  14. ↑ H. Gerstmans, L. Rodríguez-Rubio, R. Lavigne, Y. Briers: From endolysins to Artilysin®s: novel enzyme-based approaches to kill drug-resistant bacteria. In: Biochemical Society transactions. Volume 44, Number 1, February 2016, pp. 123-128, doi: 10.1042 / BST20150192 , PMID 26862197
  15. ↑ a b c V. Defraine, J. Schuermans, B. Grymonprez, SK Govers, A. Aertsen, M. Fauvart, J. Michiels, R. Lavigne, Y. Briers: Efficacy of Artilysin Art-175 against Resistant and Persistent Acinetobacter baumannii. In: Antimicrobial agents and chemotherapy. Volume 60, number 6, 06 2016, pp. 3480–3488, doi: 10.1128 / AAC.00285-16 , PMID 27021321 , PMC 4879360 (free full text).