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Molecules. 2019 May 16;24(10). pii: E1879. doi: 10.3390/molecules24101879.

The Influence of Dimerization on the Pharmacokinetics and Activity of an Antibacterial Enzyme Lysostaphin.

Author information

1
N. F. Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia. grishin-a1@yandex.ru.
2
All-Russia Research Institute of Agricultural Biotechnology, Russian Academy of Sciences, 127550 Moscow, Russia. grishin-a1@yandex.ru.
3
N. F. Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia. nvlavr@mail.ru.
4
All-Russia Research Institute of Agricultural Biotechnology, Russian Academy of Sciences, 127550 Moscow, Russia. nvlavr@mail.ru.
5
N. F. Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia. lamy13@mail.ru.
6
N. F. Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia. natalka.fanr@gmail.com.
7
N. F. Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia. keysi1986@mail.ru.
8
N. F. Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia. laurikim91@mail.ru.
9
M.V. Lomonosov Institute of Fine Chemical Technologies, MIREA Russian Technological University, 119048 Moscow, Russia. nikita1305@mail.ru.
10
N. F. Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia. boksha_irina@mail.ru.
11
Mental Health Research Center, 115522 Moscow, Russia. boksha_irina@mail.ru.
12
N. F. Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia. polyakovnb@gmail.com.
13
Vernadsky Institute of Geochemistry and Analytical Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia. polyakovnb@gmail.com.
14
N. F. Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia. gazoya@yandex.ru.
15
N. F. Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia. l.a.soboleva@yandex.ru.
16
State Research Center for Applied Microbiology and Biotechnology, 142279 Obolensk, Russia. vetchinin@obolensk.org.
17
State Research Center for Applied Microbiology and Biotechnology, 142279 Obolensk, Russia. vitpav@obolensk.org.
18
N. F. Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia. akaryagina@gmail.com.
19
All-Russia Research Institute of Agricultural Biotechnology, Russian Academy of Sciences, 127550 Moscow, Russia. akaryagina@gmail.com.
20
A. N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, 119992 Moscow, Russia. akaryagina@gmail.com.
21
N. F. Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia. lunin1955@gmail.com.
22
All-Russia Research Institute of Agricultural Biotechnology, Russian Academy of Sciences, 127550 Moscow, Russia. lunin1955@gmail.com.

Abstract

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.

KEYWORDS:

antibiotic resistance; dimerization; endolysin; lysin; lysostaphin; pharmacokinetics; staphylococcus

PMID:
31100806
DOI:
10.3390/molecules24101879
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