Friday, 28 February 2020

IMPORTANT ASPECTS OF ENZYBIOTIC THERAPY

IMPORTANT ASPECTS OF ENZYBIOTIC THERAPY

Resistance


An important feature is a function of developing resistance to certain lactic enzymes, especially lysine? This results likely from the fact that lysins interact with those components of the cell wall that are necessary for bacterial viability (Borysowski et al. 2006; Fischetti 2008 ). For instance, the receptor for S. Pneumoniae - specific lysins is choline, an essential component of the pneumococcal cell wall. In fact, in none of the hitherto conducted studies have any lysin - resistant bacteria been identified (Loeffl er et al. 2001 ). In two separate studies, both S. Pneumoniae and B. cereus failed to develop resistance to lysin even following repeated exposure to low doses of the enzyme (the same results were obtained in experiments carried out on solid media and in liquid cultures; Loeffl er et al. 2001; Schuch et al. 2002 ). B. cereus remained sensitive to lysine even after exposure to mutagens, leading to rapidly induced mutations, resulting in resistance to novobiocin and streptomycin (Schuch et al. 2002). On the other hand, it was found that bacteria during the stationary phase may be susceptible to lysine, possibly due to some changes in the cell's mural structure (Borisowski et al. 2006).

No cases of bacterial resistance to lysine have been reported so far, while four mechanisms that induce resistance to Lysosafine have been identified (Shaw et al. 2005; Gr ü Wendling et al. 2006; Kusuma et al. 2007 ). The good thing is that in some cases, the development of resistance to lipocalin in MRSA leads to increased sensitivity to methicillin and other antibiotics as well as a decrease in bacterial fitness and viruses. (Kusuma et al. 2007 ).

In addition, two common mechanisms between bacterial resistance to lysozyme have been reported. The first few components are based on the modifications made by peptidoglycan (acetyltransferase of either S - S or acetyl muramic acid residues of S - Acetylglucosine deacetylase of N - Acetylglucosine residues; Vollmer and Tom);). Another method involves the production of a lysozyme inhibitor. (Binks et al. 2005 ).

Gram-negative Bacteria


In gram-positive bacteria, peptidoglycan is readily accessible outside the cell by recombinant lytic enzymes, whereas in gram-negative bacteria it is protected by the outer membrane that is impermeable to macromolecules (Varah 1992). Therefore, gram-negative bacteria are essentially resistant to lytic enzymes. However, the results of some studies indicate that these bacteria can also be killed by recombinant lytic enzymes (Masschalck and Michiels 2003; Borysowski et al. 2006 ). For instance, two lysins were reported to be capable of killing Gram-negative bacteria (D ü ring et al. 1999; Orito et al. 2004 ). Various modifications of enzyme molecules were developed (Ibrahim et al. 2002) to enable the lytic enzyme to penetrate the outer membrane.

 Immunogenicity


One of the major factors reducing the efficacy of protein therapies is the induction of a humoral immune response (de Groot and Scott 2007). But several studies have consistently shown that specific antibodies do not completely block, but are moderately reduced, the antibacterial activity of lactic enzymes (Birozowski et al. 2006; Fischetti 2008). For instance, in a murine model of pneumococcal bacteremia, it was shown that the second dose of Cpl - 1 administered to mice i.p. 10 days after the first dose can also cure mice of infection (Jado et al. 2003 ). Similar results were obtained by Loeffl er et al. ( 2003 ), Which found that Cpl - 1 had comparable efficacy in terms of reduction in bacterial titers in the blood of naïve mice, who were given three IVs. The enzyme took the dose 4 weeks earlier, with the same study finding that preincubation of Cpl - 1 with hyperimmune rabbit serum for 10 or 60 minutes, with only a slight decrease in the lytic activity of the enzyme in vitro. (Loeffler er et al. 2003 ).

The most likely explanation for these unexpected findings is the much faster uptake of lysine to receptors on the bacterial cell wall (Fischetti 2008). These results are very important because they indicate that the apparent Immunogenesis of lysine may not significantly decrease their therapeutic efficacy after systemic administration. There are also data that do not completely neutralize specific antibodies but, to a lesser extent, the therapeutic efficacy of nucleostemin in vivo (Kilimo et al. 1998; Dajsk et al. 2002).

It is also worth noting that immunity to lactic enzymes can be reduced by adding enzyme molecules to polyethylene glycol (PEG) as shown for lysostaphin. However, it has not yet been shown that modified Lipostapin with good pharmacokinetic characteristics has high therapeutic efficacy in vivo (Walsh et al. 2003).

Safety


The major mode of the antibacterial action of lytic enzymes relies on the enzymatic cleavage of peptidoglycan, which is an exclusive component of bacterial cells. Therefore, the toxic enzyme does not adversely affect mammalian cells, at least directly. (Fischetti 2003; Borowski E;t al. 2006 ). No studies have found any serious side effects associated with the administration of a lytic enzyme to experimental animals. For instance, no signs of toxicity were detected following repeated administration of lysins to mice regardless of the route of administration (Fischetti 2003; Loeffl er et al. 2003 ). It has been noted that some Glycyglycine endopeptidases, particularly lysostaphin, had to degrade elastin, which has a high content of glycine residues (Park et al. 1995). This suggests that Lysosafine (and perhaps other peptidases) cleave other proteins present in mammalian tissues. It remains to be verified whether this activity can alter any side effects of the lactic enzyme.

Another important aspect of the safety of antibiotic therapy is the possibility of the release of different proinflammatory components from bacterial cells being lysed. Theoretically, the massive release of these components could lead to septic shock and multiple organ failure (Nau and Eiffert 2002 ). However, many experimental studies have consistently shown that even massive bacteriolysis during the treatment of systemic bacterial infections, including bacteremia, does not result in any serious side effects. For instance, practically no side effects were found following treatment of bacteremic animals with lysins and lysostaphin, which rapidly reduced bacterial titers in the blood (Jado et al. 2003; Loeffl er et al. 2003; Kokai - Kun et al. 2007 ).

Moreover, side effects associated with antibiotic therapy might occur following the massive release of preformed bacterial toxins from the cytoplasm of bacteria during bacteriolysis. In fact, autolysin in bacterial species may be involved in the pathogenesis of infection in the method based on the release of various toxins. For instance, autolysins of Clostridium may be involved in the release of toxin A and toxin B (Dhalluin et al. 2005 ). This potential effect should also be taken into account in the discussion about the safety of enzymatic therapy.


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