Citation:
Angew Chem Int Ed Engl. 2024 Feb 26:e202402405. doi: 10.1002/anie.202402405. Online ahead of print
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. 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.
Epub:
Not Epub
Link to Publication:
https://onlinelibrary.wiley.com/doi/10.1002/anie.202402405
Organism or Cell Type:
Escherichia coli K12 MG1655 and Acinetobacter baumannii (ATCC19606)
Delivery Method:
siderophore conjugate