The influence of dimerization on the pharmacokinetics and activity of an antibacterial enzyme lysostaphinстатья
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Дата последнего поиска статьи во внешних источниках: 26 июня 2019 г.
Аннотация:The increasing prevalence of antibiotic-resistant strains of pathogenic bacteria is a major
healthcare problem. Antibacterial lysins are enzymes that cleave the peptidoglycan of the bacterial cell wall. These proteins hold potential as a supplement or an alternative to traditional antibiotics since they are active against antibiotic resistant strains. However, antibacterial lysins are rapidly eliminated from the systemic circulation, which limits their application. Dimerization of an anti-pneumococcal lysin Cpl-1 has been demonstrated to decrease the clearance rate of this protein in mice. In the present work, we constructed a dimer of an anti-staphylococcal lysin lysostaphin by fusing it
with an anti-parallel α-helical dimerization domain. Lysostaphin dimer had a more favorable
pharmacokinetic profile with increased terminal half-life and area under the curve (AUC) values
compared to monomeric lysostaphin. However, the staphylolytic activity of dimerized lysostaphin
was decreased. This decrease in activity was likely caused by the dimerization; since the catalytic
efficacy of lysostaphin dimer towards pentaglycine peptide was unaltered. Our results demonstrate
that, although dimerization is indeed beneficial for the pharmacokinetics of antibacterial lysins, this
approach might not be suitable for all lysins, as it can negatively affect the lysin activity.