Targeting Bacterial Adenylate Kinase mRNA with a Chimeric Antisense Oligonucleotide for Rational Antibacterial Drug...

Area of Science:

• Antimicrobial drug discovery
• Molecular biology
• Bacterial genetics

Background:

• Antibiotic resistance is a growing global health crisis, outpacing new drug development.
• Existing antibiotic pipelines are insufficient to meet the demand for new treatments.
• Novel strategies are urgently needed to develop effective antibacterial agents.

Purpose of the Study:

• To present a rational approach for discovering antibacterial drugs.
• To investigate the efficacy of chimeric antisense oligonucleotides (ASOs) targeting adenylate kinase mRNA in *Staphylococcus aureus*.
• To evaluate the delivery of ASOs using the cell-penetrating oligopeptide pVEC.

Main Methods:

• Development of chimeric antisense oligonucleotide (ASO) targeting adenylate kinase mRNA.
• Delivery of ASO into *Staphylococcus aureus* using cell-penetrating oligopeptide pVEC.
• Assessment of bactericidal activity and minimal inhibitory concentration (MIC) of the pVEC-ASO1 conjugate.
• Evaluation of cell line survivability to determine safety profile.

Main Results:

• The pVEC-ASO1 conjugate demonstrated a bactericidal effect against *Staphylococcus aureus*.
• The minimal inhibitory concentration (MIC50) was determined to be 500 nM.
• High survivability (98%) was observed in cell lines at the effective concentration of pVEC-ASO1.
• This marks the fifth successful bacterial mRNA target using the pVEC-ASO delivery system.

Conclusions:

• Chimeric ASOs targeting bacterial mRNA, delivered via pVEC, represent a promising strategy for antibacterial drug discovery.
• The pVEC-ASO1 conjugate is a potential drug candidate against *Staphylococcus aureus* infections.
• The targeting of the coding region of mRNA broadens the therapeutic applications of this approach for various bacterial pathogens.