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Development of novel antimicrobials with engineered endolysin LysECD7-SMAP to combat Gram-negative bacterial infections
DV. Vasina, NP. Antonova, VA. Gushchin, AV. Aleshkin, MV. Fursov, AD. Fursova, PG. Gancheva, IV. Grigoriev, P. Grinkevich, AV. Kondratev, AV. Kostarnoy, AM. Lendel, VV. Makarov, MA. Nikiforova, AA. Pochtovyi, T. Prudnikova, TA. Remizov, NV....
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články
Grantová podpora
Contract no. 0373100122120000008 of 08 April 2020
Centre for Strategic Planning and Management of Biomedical Health Risks of the Federal Medical Biological Agency
no. 0373100122119000013 of 15 May 2019
Centre for Strategic Planning and Management of Biomedical Health Risks of the Federal Medical Biological Agency
NLK
BioMedCentral
od 2008-12-01
BioMedCentral Open Access
od 2009
Directory of Open Access Journals
od 2009
Free Medical Journals
od 2009
PubMed Central
od 2009
Europe PubMed Central
od 2009
ProQuest Central
od 2009-01-01
Open Access Digital Library
od 2009-01-01
Open Access Digital Library
od 2009-01-01
Medline Complete (EBSCOhost)
od 1998-01-01
Health & Medicine (ProQuest)
od 2009-01-01
ROAD: Directory of Open Access Scholarly Resources
od 1994
Springer Nature OA/Free Journals
od 2008-12-01
- MeSH
- antibakteriální látky farmakologie aplikace a dávkování MeSH
- endopeptidasy * farmakologie aplikace a dávkování MeSH
- gramnegativní bakteriální infekce * farmakoterapie MeSH
- gramnegativní bakterie * účinky léků MeSH
- krysa rodu rattus MeSH
- myši inbrední BALB C * MeSH
- myši MeSH
- proteinové inženýrství metody MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Among the non-traditional antibacterial agents in development, only a few targets critical Gram-negative bacteria such as carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii or cephalosporin-resistant Enterobacteriaceae. Endolysins and their genetically modified versions meet the World Health Organization criteria for innovation, have a novel mode of antibacterial action, no known bacterial cross-resistance, and are being intensively studied for application against Gram-negative pathogens. METHODS: The study presents a multidisciplinary approach, including genetic engineering of LysECD7-SMAP and production of recombinant endolysin, its analysis by crystal structure solution following molecular dynamics simulations and evaluation of antibacterial properties. Two types of antimicrobial dosage forms were formulated, resulting in lyophilized powder for injection and hydroxyethylcellulose gel for topical administration. Their efficacy was estimated in the treatment of sepsis, and pneumonia models in BALB/c mice, diabetes-associated wound infection in the leptin receptor-deficient db/db mice and infected burn wounds in rats. RESULTS: In this work, we investigate the application strategies of the engineered endolysin LysECD7-SMAP and its dosage forms evaluated in preclinical studies. The catalytic domain of the enzyme shares the conserved structure of endopeptidases containing a putative antimicrobial peptide at the C-terminus of polypeptide chain. The activity of endolysins has been demonstrated against a range of pathogens, such as Klebsiella pneumoniae, A. baumannii, P. aeruginosa, Staphylococcus haemolyticus, Achromobacter spp, Burkholderia cepacia complex and Haemophylus influenzae, including those with multidrug resistance. The efficacy of candidate dosage forms has been confirmed in in vivo studies. Some aspects of the interaction of LysECD7-SMAP with cell wall molecular targets are also discussed. CONCLUSIONS: Our studies demonstrate the potential of LysECD7-SMAP therapeutics for the systemic or topical treatment of infectious diseases caused by susceptible Gram-negative bacterial species and are critical to proceed LysECD7-SMAP-based antimicrobials trials to advanced stages.
Faculty of Biology Lomonosov Moscow State University Moscow Russia
Faculty of Science University of South Bohemia in Ceske Budejovice Ceske Budejovice Czech Republic
G N Gabrichevsky Moscow Research Institute for Epidemiology and Microbiology Moscow Russia
Russian Medical Academy of Continuing Professional Education Ministry of Public Health Moscow Russia
State Research Center for Applied Microbiology and Biotechnology Obolensk Russia
Citace poskytuje Crossref.org
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