Design and off-target prediction for antisense oligomers targeting bacterial mRNAs with the MASON web server

Antisense oligomers (ASOs), such as peptide nucleic acids (PNAs), designed to inhibit the translation of essential bacterial genes, have emerged as attractive sequence- and species-specific programmable RNA antibiotics. Yet, potential drawbacks include unwanted side effects caused by their binding t...

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Bibliographic Details
Published in:RNA (Cambridge) 2023-05, Vol.29 (5), p.570-583
Main Authors: Jung, Jakob, Popella, Linda, Do, Phuong Thao, Pfau, Patrick, Vogel, Jörg, Barquist, Lars
Format: Article
Language:English
Subjects:
Antibiotics
Antisense RNA
Bacteria
Bacteria - genetics
Bioinformatics
Internet
Nucleotide sequence
Oligomers
Oligonucleotides, Antisense - pharmacology
Peptide nucleic acids
Peptide Nucleic Acids - chemistry
Peptide Nucleic Acids - genetics
Peptide Nucleic Acids - pharmacology
Ribonucleic acid
RNA
RNA, Messenger - chemistry
RNA, Messenger - genetics
Salmonella
Salmonella typhimurium - genetics
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Summary:Antisense oligomers (ASOs), such as peptide nucleic acids (PNAs), designed to inhibit the translation of essential bacterial genes, have emerged as attractive sequence- and species-specific programmable RNA antibiotics. Yet, potential drawbacks include unwanted side effects caused by their binding to transcripts other than the intended target. To facilitate the design of PNAs with minimal off-target effects, we developed MASON ( ake nti ense ligomers ow), a web server for the design of PNAs that target bacterial mRNAs. MASON generates PNA sequences complementary to the translational start site of a bacterial gene of interest and reports critical sequence attributes and potential off-target sites. We based MASON's off-target predictions on experiments in which we treated serovar Typhimurium with a series of 10-mer PNAs derived from a PNA targeting the essential gene but carrying two serial mismatches. Growth inhibition and RNA-sequencing (RNA-seq) data revealed that PNAs with terminal mismatches are still able to target , suggesting wider off-target effects than anticipated. Comparison of these results to an RNA-seq data set from uropathogenic (UPEC) treated with eleven different PNAs confirmed that our findings are not unique to We believe that MASON's off-target assessment will improve the design of specific PNAs and other ASOs.
ISSN:1355-8382
1469-9001
DOI:10.1261/RNA.079263.122