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Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases

Current antibiotics tend to be broad spectrum, leading to indiscriminate killing of commensal bacteria and accelerated evolution of drug resistance. Here, we use CRISPR-Cas technology to create antimicrobials whose spectrum of activity is chosen by design. RNA-guided nucleases (RGNs) targeting speci... Full description

Journal Title: Nature biotechnology 2014-11, Vol.32 (11), p.1141-1145
Main Author: Citorik, Robert J
Other Authors: Mimee, Mark , Lu, Timothy K
Format: Electronic Article Electronic Article
Language: English
Subjects:
RNA
Publisher: United States: Nature Publishing Group
ID: ISSN: 1087-0156
Link: https://www.ncbi.nlm.nih.gov/pubmed/25240928
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4237163
title: Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases
format: Article
creator:
  • Citorik, Robert J
  • Mimee, Mark
  • Lu, Timothy K
subjects:
  • Anti-Bacterial Agents - therapeutic use
  • Anti-Infective Agents - therapeutic use
  • Antibiotics
  • Article
  • Bacteriophages - genetics
  • Base Sequence - genetics
  • Biotechnology
  • Carbapenems - therapeutic use
  • CRISPR-Cas Systems
  • Drug resistance in microorganisms
  • Drug Resistance, Microbial - genetics
  • Enterobacteriaceae
  • Enterohemorrhagic Escherichia coli - genetics
  • Enterohemorrhagic Escherichia coli - pathogenicity
  • Enzymes
  • Escherichia coli
  • Galleria mellonella
  • Gene Targeting
  • Genetic aspects
  • Genetic research
  • Health aspects
  • Pharmaceutical research
  • Plasmids
  • Ribonucleases - genetics
  • Ribonucleic acid
  • RNA
  • RNA sequencing
  • RNA, Guide - genetics
ispartof: Nature biotechnology, 2014-11, Vol.32 (11), p.1141-1145
description: Current antibiotics tend to be broad spectrum, leading to indiscriminate killing of commensal bacteria and accelerated evolution of drug resistance. Here, we use CRISPR-Cas technology to create antimicrobials whose spectrum of activity is chosen by design. RNA-guided nucleases (RGNs) targeting specific DNA sequences are delivered efficiently to microbial populations using bacteriophage or bacteria carrying plasmids transmissible by conjugation. The DNA targets of RGNs can be undesirable genes or polymorphisms, including antibiotic resistance and virulence determinants in carbapenem-resistant Enterobacteriaceae and enterohemorrhagic Escherichia coli. Delivery of RGNs significantly improves survival in a Galleria mellonella infection model. We also show that RGNs enable modulation of complex bacterial populations by selective knockdown of targeted strains based on genetic signatures. RGNs constitute a class of highly discriminatory, customizable antimicrobials that enact selective pressure at the DNA level to reduce the prevalence of undesired genes, minimize off-target effects and enable programmable remodeling of microbiota.
language: eng
source:
identifier: ISSN: 1087-0156
fulltext: no_fulltext
issn:
  • 1087-0156
  • 1546-1696
url: Link


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descriptionCurrent antibiotics tend to be broad spectrum, leading to indiscriminate killing of commensal bacteria and accelerated evolution of drug resistance. Here, we use CRISPR-Cas technology to create antimicrobials whose spectrum of activity is chosen by design. RNA-guided nucleases (RGNs) targeting specific DNA sequences are delivered efficiently to microbial populations using bacteriophage or bacteria carrying plasmids transmissible by conjugation. The DNA targets of RGNs can be undesirable genes or polymorphisms, including antibiotic resistance and virulence determinants in carbapenem-resistant Enterobacteriaceae and enterohemorrhagic Escherichia coli. Delivery of RGNs significantly improves survival in a Galleria mellonella infection model. We also show that RGNs enable modulation of complex bacterial populations by selective knockdown of targeted strains based on genetic signatures. RGNs constitute a class of highly discriminatory, customizable antimicrobials that enact selective pressure at the DNA level to reduce the prevalence of undesired genes, minimize off-target effects and enable programmable remodeling of microbiota.
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subjectAnti-Bacterial Agents - therapeutic use ; Anti-Infective Agents - therapeutic use ; Antibiotics ; Article ; Bacteriophages - genetics ; Base Sequence - genetics ; Biotechnology ; Carbapenems - therapeutic use ; CRISPR-Cas Systems ; Drug resistance in microorganisms ; Drug Resistance, Microbial - genetics ; Enterobacteriaceae ; Enterohemorrhagic Escherichia coli - genetics ; Enterohemorrhagic Escherichia coli - pathogenicity ; Enzymes ; Escherichia coli ; Galleria mellonella ; Gene Targeting ; Genetic aspects ; Genetic research ; Health aspects ; Pharmaceutical research ; Plasmids ; Ribonucleases - genetics ; Ribonucleic acid ; RNA ; RNA sequencing ; RNA, Guide - genetics
ispartofNature biotechnology, 2014-11, Vol.32 (11), p.1141-1145
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abstractCurrent antibiotics tend to be broad spectrum, leading to indiscriminate killing of commensal bacteria and accelerated evolution of drug resistance. Here, we use CRISPR-Cas technology to create antimicrobials whose spectrum of activity is chosen by design. RNA-guided nucleases (RGNs) targeting specific DNA sequences are delivered efficiently to microbial populations using bacteriophage or bacteria carrying plasmids transmissible by conjugation. The DNA targets of RGNs can be undesirable genes or polymorphisms, including antibiotic resistance and virulence determinants in carbapenem-resistant Enterobacteriaceae and enterohemorrhagic Escherichia coli. Delivery of RGNs significantly improves survival in a Galleria mellonella infection model. We also show that RGNs enable modulation of complex bacterial populations by selective knockdown of targeted strains based on genetic signatures. RGNs constitute a class of highly discriminatory, customizable antimicrobials that enact selective pressure at the DNA level to reduce the prevalence of undesired genes, minimize off-target effects and enable programmable remodeling of microbiota.
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