Fusion of Lysostaphin to an Albumin Binding Domain Prolongs Its Half-Life and Bactericidal Activity in the Systemic Circulation
AbstractAntibacterial lysins are promising proteins that are active against both antibiotic-susceptible and antibiotic-resistant bacterial strains. However, a major limitation of antibacterial lysins is their fast elimination from systemic circulation. PEGylation increases the plasma half-life of lysins but renders them inactive. Here we report the construction of a fusion protein of lysostaphin, a potent anti-staphylococcal lysin, and an albumin-binding domain from streptococcal protein G. The resulting fusion protein was less active than the parent enzyme lysostaphin, but it still retained significant antibacterial activity even when bound to serum albumin. The terminal half-life of the fusion protein in rats was five-fold greater than that of lysostaphin (7.4 vs. 1.5 h), and the area under the curve increased more than 115 times. Most importantly, this increase in systemic circulation time compensated for the decrease in activity. The plasma from rats that received an injection of the fusion protein retained bactericidal activity for up to 7 h, while plasma from rats that received plain lysostaphin lacked any detectable activity after 4 h. To the best of our knowledge, this is the first report of an antibacterial lysin with both improved pharmacokinetic parameters and prolonged bactericidal activity in the systemic circulation. View Full-Text
- Supplementary File 1:
ZIP-Document (ZIP, 4859 KB)
Share & Cite This Article
Grishin, A.V.; Shestak, N.V.; Lavrova, N.V.; Lyashchuk, A.M.; Popova, L.I.; Strukova, N.V.; Generalova, M.S.; Ryazanova, A.V.; Polyakov, N.B.; Galushkina, Z.M.; Soboleva, L.A.; Boksha, I.S.; Karyagina, A.S.; Lunin, V.G. Fusion of Lysostaphin to an Albumin Binding Domain Prolongs Its Half-Life and Bactericidal Activity in the Systemic Circulation. Molecules 2019, 24, 2892.
Grishin AV, Shestak NV, Lavrova NV, Lyashchuk AM, Popova LI, Strukova NV, Generalova MS, Ryazanova AV, Polyakov NB, Galushkina ZM, Soboleva LA, Boksha IS, Karyagina AS, Lunin VG. Fusion of Lysostaphin to an Albumin Binding Domain Prolongs Its Half-Life and Bactericidal Activity in the Systemic Circulation. Molecules. 2019; 24(16):2892.Chicago/Turabian Style
Grishin, Alexander V.; Shestak, Nikita V.; Lavrova, Natalia V.; Lyashchuk, Alexander M.; Popova, Liubov I.; Strukova, Natalia V.; Generalova, Maria S.; Ryazanova, Anna V.; Polyakov, Nikita B.; Galushkina, Zoya M.; Soboleva, Lyubov A.; Boksha, Irina S.; Karyagina, Anna S.; Lunin, Vladimir G. 2019. "Fusion of Lysostaphin to an Albumin Binding Domain Prolongs Its Half-Life and Bactericidal Activity in the Systemic Circulation." Molecules 24, no. 16: 2892.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.