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Siderophore-Mediated Conveyance of Antibacterial-Antisense Oligomers

Pals, M. J.; Wijnberg, L.; Yildiz, C.; Velema, W.

2023-10-30 microbiology
10.1101/2023.10.30.564798 bioRxiv
Show abstract

Antibacterial resistance is a major threat for human health. There is a need for new antibacterials to stay ahead of constantly-evolving resistant bacteria. Antibiotic antisense oligomers hold promise as powerful next-generation antibiotics, but issues with their delivery hamper their applicability. Here, we exploit the siderophore-mediated iron uptake pathway to efficiently transport antisense oligomers into bacteria. We appended a synthetic siderophore to antisense oligomers targeting the essential acpP gene in Escherichia coli. Siderophore-conjugated morpholino and PNA antisense oligomers displayed potent antibacterial properties. Conjugates bearing a minimal siderophore consisting of a mono-catechol group showed equally effective. Targeting the lacZ transcript resulted in dose-dependent decreased {beta}-galactosidase production, demonstrating selective protein downregulation. Whole-genome sequencing of resistant mutants and competition experiments with the endogenous siderophore verified selective uptake through the siderophore-mediated iron uptake pathway. Lastly, no toxicity towards mammalian cells was found. Collectively, our work provides a convenient approach for delivering antisense oligomers into bacteria.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.