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Peptide nucleic acid restores colistin susceptibility through modulation of MCR-1 expression in Escherichia coli.
- Source :
-
Journal of Antimicrobial Chemotherapy (JAC) . Aug2020, Vol. 75 Issue 8, p2059-2065. 7p. - Publication Year :
- 2020
-
Abstract
- <bold>Background: </bold>Plasmid-mediated mechanisms of drug resistance accelerate the spread of polymyxin resistance, leaving clinicians with few or no antibacterial options for the treatment of infections caused by MDR bacteria, especially carbapenemase-producing strains.<bold>Objectives: </bold>To evaluate the associations among promoter sequence variation, mcr-1 expression, host factors and levels of colistin resistance and to propose antisense agents such as peptide nucleic acids (PNAs) targeting mcr-1 as a tool to restore colistin susceptibility through modulation of MCR-1 expression in Escherichia coli.<bold>Methods: </bold>A β-galactosidase assay was performed to study mcr-1 promoter activity. Quantitative real-time PCR and western blot assays were used to identify the expression level of MCR-1 in WT strains and transformants. Three PNAs targeting different regions of mcr-1 were designed and synthesized to determine whether they can effectively inhibit MCR-1 expression. MIC was measured to test colistin susceptibility in the presence or absence of PNA-1 in mcr-1-carrying E. coli.<bold>Results: </bold>Variation in the mcr-1 promoter sequence and host species affect promoter activity, MCR-1 expression levels and colistin MICs. One PNA targeting the ribosome-binding site fully inhibited the expression of mcr-1 at a concentration of 4 μM, resulting in significantly increased susceptibility to colistin. The MIC90 of colistin decreased from 8 to 2 mg/L (P < 0.05) in the presence of 4 μM PNA.<bold>Conclusions: </bold>These findings suggest that the antisense approach is a possible strategy to combat mcr-1-mediated resistance as well as other causes of emerging global resistance. [ABSTRACT FROM AUTHOR]
- Subjects :
- *COLISTIN
*PEPTIDE nucleic acids
*ESCHERICHIA coli
*PROTEINS
*RESEARCH
*RESEARCH methodology
*MEDICAL cooperation
*EVALUATION research
*COMPARATIVE studies
*ESCHERICHIA coli diseases
*GENES
*DRUG resistance in microorganisms
*NUCLEIC acids
*ANTIBIOTICS
*MICROBIAL sensitivity tests
*PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 03057453
- Volume :
- 75
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- Journal of Antimicrobial Chemotherapy (JAC)
- Publication Type :
- Academic Journal
- Accession number :
- 144669090
- Full Text :
- https://doi.org/10.1093/jac/dkaa140