Nonviral Genome Editing Based on a Polymer-Derivatized CRISPR Nanocomplex for Targeting Bacterial Pathogens and Antibiotic Resistance

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The overuse of antibiotics plays a major role in the emergence and spread of multidrug-resistant bacteria. A molecularly targeted, specific treatment method for bacterial pathogens can prevent this problem by reducing the selective pressure during microbial growth. Herein, we introduce a nonviral treatment strategy delivering genome editing material for targeting antibacterial resistance. We apply the CRISPR-Cas9 system, which has been recognized as an innovative tool for highly specific and efficient genome engineering in different organisms, as the delivery cargo. We utilize polymer-derivatized Cas9, by direct covalent modification of the protein with cationic polymer, for subsequent complexation with single-guide RNA targeting antibiotic resistance. We show that nanosized CRISPR complexes (= Cr-Nanocomplex) were successfully formed, while maintaining the functional activity of Cas9 endonuclease to induce double-strand DNA cleavage. We also demonstrate that the Cr-Nanocomplex designed to target mecA-the major gene involved in methicillin resistance-can be efficiently delivered into Methicillin-resistant Staphylococcus aureus (MRSA), and allow the editing of the bacterial genome with much higher efficiency compared to using native Cas9 complexes or conventional lipid-based formulations. The present study shows for the first time that a covalently modified CRISPR system allows nonviral, therapeutic genome editing, and can be potentially applied as a target specific antimicrobial.
Publisher
AMER CHEMICAL SOC
Issue Date
2017-04
Language
English
Article Type
Article
Keywords

VIVO GENE DELIVERY; IN-VIVO; STAPHYLOCOCCUS-AUREUS; VANCOMYCIN-RESISTANT; EFFICIENT DELIVERY; VIRAL VECTORS; THERAPY; POLYETHYLENIMINE; NANOPARTICLES; RNA

Citation

BIOCONJUGATE CHEMISTRY, v.28, no.4, pp.957 - 967

ISSN
1043-1802
DOI
10.1021/acs.bioconjchem.6b00676
URI
http://hdl.handle.net/10203/223860
Appears in Collection
BS-Journal Papers(저널논문)NT-Journal Papers(저널논문)
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