The Influence of Dimerization on the Pharmacokinetics and Activity of an Antibacterial Enzyme Lysostaphin
| Autor: | Anna S. Karyagina, Vladimir G. Lunin, N V Lavrova, Maria S. Generalova, Nikita V. Shestak, Vitaliy M Pavlov, Anna V. Ryazanova, Sergey S Vetchinin, N V Strukova, Z. M. Galushkina, A. V. Grishin, Lyubov’ A. Soboleva, I. S. Boksha, N. B. Polyakov, A. M. Lyashchuk |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular antibiotic resistance Protein Conformation medicine.drug_class Antibiotics Lysin Pharmaceutical Science Peptide Microbial Sensitivity Tests medicine.disease_cause complex mixtures Catalysis Article Bacterial cell structure Analytical Chemistry lcsh:QD241-441 03 medical and health sciences chemistry.chemical_compound lcsh:Organic chemistry Drug Discovery medicine Amino Acid Sequence lysin Physical and Theoretical Chemistry 030304 developmental biology chemistry.chemical_classification 0303 health sciences dimerization 030306 microbiology Lysostaphin Organic Chemistry Pathogenic bacteria Anti-Bacterial Agents Enzyme Activation Enzyme chemistry Biochemistry Chemistry (miscellaneous) Area Under Curve endolysin bacteria Molecular Medicine lysostaphin Peptidoglycan Protein Multimerization staphylococcus pharmacokinetics |
| Zdroj: | Molecules, Vol 24, Iss 10, p 1879 (2019) Molecules Volume 24 Issue 10 |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules24101879 |
| Popis: | 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 &alpha 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. |
| Databáze: | OpenAIRE |
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