Catechol-Siderophore Mimics Convey Nucleic Acid Therapeutics into Bacteria

Area of Science:

• Microbiology
• Molecular Biology
• Drug Delivery

Background:

• Antibacterial resistance poses a significant global health threat, necessitating the development of novel antimicrobial agents.
• Nucleic acid therapeutics offer potential as antibiotics, but efficient bacterial delivery remains a challenge.

Purpose of the Study:

• To develop a novel delivery system for nucleic acid therapeutics into bacteria using the siderophore-mediated iron uptake pathway.
• To evaluate the antibacterial efficacy and specificity of synthetic siderophore-conjugated antisense oligomers against resistant bacteria.

Main Methods:

• Synthetic siderophores were conjugated to antisense oligomers (PNA and PMO) targeting essential bacterial genes.
• Antibacterial activity was assessed against Escherichia coli and Acinetobacter baumannii.
• Mechanisms of uptake were verified using whole-genome sequencing and competition experiments.
• Mammalian cell toxicity was evaluated.

Main Results:

• Siderophore-conjugated antisense oligomers demonstrated potent antibacterial activity against resistant bacteria.
• Targeting the lacZ transcript led to dose-dependent reduction in protein production, indicating selective gene silencing.
• Minimal siderophore conjugates were as effective as complex ones.
• Selective uptake via the iron uptake pathway was confirmed.
• No toxicity was observed in mammalian cells.

Conclusions:

• Synthetic siderophore mimics can efficiently deliver nucleic acid therapeutics into bacteria.
• This strategy represents a promising new avenue for developing effective antibacterial agents against resistant pathogens.
• The approach is specific and safe for mammalian cells.