Details

Autor(en) / Beteiligte

• Pals, Mathijs J.
• Wijnberg, Luuk
• Yildiz, Çağlar
• Velema, Willem A.

Titel

Catechol‐Siderophore Mimics Convey Nucleic Acid Therapeutics into Bacteria

Ist Teil von

• Angewandte Chemie (International ed.), 2024-05, Vol.63 (19), p.e202402405-n/a

Auflage

International ed. in English

Ort / Verlag

Germany: Wiley Subscription Services, Inc

Erscheinungsjahr

2024

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Antibacterial resistance is a major threat for human health. There is a need for new antibacterials to stay ahead of constantly‐evolving resistant bacteria. Nucleic acid therapeutics hold promise as powerful 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 PNA and PMO 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 β‐galactosidase production, demonstrating selective protein downregulation. Applying this concept to Acinetobacter baumannii also showed concentration‐dependent growth inhibition. 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, we demonstrate for the first time that large nucleic acid therapeutics can be efficiently transported into bacteria using synthetic siderophore mimics. Synthetic siderophores are conjugated to antibacterial antisense sequences to efficiently deliver them into bacteria. The conjugates display effective protein downregulation and potent antibacterial properties. Whole‐genome sequencing of resistant mutants and competition experiments with the endogenous siderophore demonstrate transport through the siderophore‐mediated iron uptake pathway.