Can Vitamin B12 Assist the Internalization of Antisense LNA Oligonucleotides into Bacteria?

The emergence of bacterial resistance to traditional small-molecule antibiotics is fueling the search for innovative strategies to treat infections. Inhibiting the expression of essential bacterial genes using antisense oligonucleotides (ASOs), particularly composed of nucleic acid mimics (NAMs), ha...

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Bibliographic Details
Published in:Antibiotics (Basel) 2021-04, Vol.10 (4), p.379
Main Authors: Pereira, Sara, Yao, Ruwei, Gomes, Mariana, Jørgensen, Per Trolle, Wengel, Jesper, Azevedo, Nuno Filipe, Sobral Santos, Rita
Format: Article
Language:English
Subjects:
2′OMe
Alkynes
antibacterial drug
Antibiotics
Antisense oligonucleotides
Bacteria
Biofilms
Biological effects
Conjugates
Cyanocobalamin
Cytosol
E coli
Gene expression
In vivo methods and tests
Internalization
LNA
Localization
nucleic acid mimics
Nucleic acids
Oligonucleotides
Peptides
Proteins
RNA polymerase
Vitamin B12
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Summary:The emergence of bacterial resistance to traditional small-molecule antibiotics is fueling the search for innovative strategies to treat infections. Inhibiting the expression of essential bacterial genes using antisense oligonucleotides (ASOs), particularly composed of nucleic acid mimics (NAMs), has emerged as a promising strategy. However, their efficiency depends on their association with vectors that can translocate the bacterial envelope. Vitamin B is among the largest molecules known to be taken up by bacteria and has very recently started to gain interest as a trojan-horse vector. Gapmers and steric blockers were evaluated as ASOs against ( ). Both ASOs were successfully conjugated to B by copper-free azide-alkyne click-chemistry. The biological effect of the two conjugates was evaluated together with their intracellular localization in . Although not only B but also both B -ASO conjugates interacted strongly with , they were mostly colocalized with the outer membrane. Only 6-9% were detected in the cytosol, which showed to be insufficient for bacterial growth inhibition. These results suggest that the internalization of B -ASO conjugates is strongly affected by the low uptake rate of the B in and that further studies are needed before considering this strategy against biofilms in vivo.
ISSN:2079-6382
2079-6382
DOI:10.3390/antibiotics10040379