Summary

The worrying and increasing development of bacterial resistance due to overuse has made that alternative strategies to the therapeutic use of antibiotics are sought. One of them is the application of phage-encoded lytic proteins. This is a technology that can quickly eliminate specific pathogens and prevent the emergence of multidrug resistance.

Bacterial resistance is a growing phenomenon. It consists of the partial or total refraction of microorganisms to the effect of an antibiotic treatment (1). This is mainly due to the overuse of antibiotics. Bacterial resistance towards antibiotics is one of the main challenges in the field of modern medicine which leads the Scientifics to the search of new alternatives.

In order to overcome the obstacles related to the bacterial resistance, the number of therapies and alternatives is growing in a significant way (2). One of the solutions under investigation is the use of lysis enzymes of bacteriophages that infect and kill the bacteria. After its replication within the host, the phage encounters an issue: it is necessary to leave the bacteria in order to disseminate its progeny. In this regard, the phages have developed a lytic system that undermines the bacterial cellular wall, which leads to the bacterial lysis. The lysis enzimes of phages, also known as lysines, are highly efficient molecules which have experimented a remarkable improvement all over the years with this purpose.

Scientifics have been well aware of the phage lysis activity for almost one century. Whole phages have been used with the aim to control infections. However, the use of their lytic enzymes, known as endolysins, has recently started being used as a mechanism to control the pathogenic bacteria which are resistant to antibiotics. (3). These enzymes when are used for the treatment of infectious diseases are called enzybiotics. In the year 2001, this term was used for the first time by Nelson et al.

Research shows that lysines work only with Gram-positive bacteria, since they are able to make direct contact with the peptidoglycan when it is exogenously added. However, the external layer of Gram-negative bacteria does not allow this interaction to take place. This can be avoided by using destabilizing agents which enable the entrance of these lysine (4). At the beginning of 2014, the National Institute of Allergy and Infectious Diseases (NIAID) highlighted the phage therapy as one of the 7 key elements in the fight against the bacterial resistance. This fact explains the importance of this new line of research.

Due to the concern created by the multiple resistance, antibiotics are not suitable for controlling the carrier status of pathogenic bacteria. However, the fact of reducing or eliminating this reservoir for human pathogens in controlled environments (such as hospitals and retirement homes) would lead to a significant decrease of certain diseases (5). In this regard, there is a number of research groups, such as the one leaded by Dr. Pedro García at the CIB-CSIC and the one from Professor Vincent A. Fischetti at the Rockefeller University in New York. They are studying phage lysines, either natural or synthetic, in order to prevent infections and/or eliminate pathogenic bacteria (e.g. Streptococcus pneumoniae or Staphylococcus aureus) in a targeted manner. For instance, the synthetic enzyme Cpl-711 (which is a combination of different phage enzymes) is able to eliminate efficiently infections which are caused by the pathogen Streptococcus pneumoniae in a few hours, both on mice and zebrafish (6). Such enzymes can be administered, either through the nose or parenterally, to control the organisms in the environment, houses and hospitals in order to prevent or reduce serious infections caused by bacteria. Nowadays, no other biologic compounds are able to eliminate these bacteria in such a quick manner.

To summarize, the acquired knowledge on the physical-chemical characteristics of the lysines could be used with the aim of achieving the enzybiotics highest level of activity towards the susceptible pathogens. Due to the great abundance of potential enzybiotics, along with the high amount of phages in the environment and the favorable combination of these proteins, it is foreseeable that customized enzymes can be created for specific pathogens. This is especially remarkable for those cases of pathogens which are highly resistant to the existing antibiotics (7). Furthermore, it is likely that some modules can be combined within the upcoming years in order to create new enzymes which are efficient towards the pathogen or group of pathogens involved in a specific infection in the surrounding microbiota.

Referencias

1. http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf
2. http://www.nature.com/polopoly_fs/1.17621!/menu/main/topColumns/topLeftColumn/pdf/521402a.pdf
3. http://aac.asm.org/content/57/11/5355.full.pdf+html
4. Díez-Martínez R, de Paz HD, Bustamante N, García E, Menéndez M, García P (2013) Improving the lethal effect of Cpl-7, a pneumococcal phage lysozyme with broad bactericidal activity, by inverting the net charge of its cell wall-binding module. Antimicrob. Agents Chemother. 57: 5355–5365. doi:10.1128/AAC.01372-13. http://aac.asm.org/content/57/11/5355.full.pdf+html
5. http://centennial.rucares.org/index.php?page=Phage_Lysins
6. R Díez-Martínez, HD De Paz, E García-Fernández, N Bustamante, Euler CW, Fischetti VA, Menendez M, García P (2015). A novel chimeric phage lysin with high in vitro and in vivo bactericidal activity against Streptococcus pneumoniae. J. Antimicrob. Chemother. 70:1763–1773. doi: 10.1093/jac/dkv038. https://www.researchgate.net/publication/271522791_A_novel_chimeric_phage_lysin_with_high_in_vitro_and_in_vivo_bactericidal_activity_against_Streptococcus_pneumoniae
7. M Schmelcher, DM Donovan and MJ Loessner (2012). Bacteriophage endolysins as novel antimicrobials. Future Microbiol. 7:1147–1171. doi: 10.2217/fmb.12.97. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563964/

Fuente: Sociedad Española de Bioquímica y Biología Molecular

Roberto Díez-Martínez

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