Design and applications of chimeric antisense oligonucleotides that bind TPP mRNAs as antibacterial agents.

Abstract

The rapid emergence of antibiotic-resistant bacteria has created an urgent need for innovative therapeutic strategies that go beyond conventional small-molecule antibiotics. Among the most promising approaches is the use of nucleic acid-based therapeutics, particularly antisense oligonucleotides (ASOs), which offer high specificity in targeting essential bacterial genes at the mRNA level. Chimeric ASOs represent an advanced generation of ASOs, engineered by combining different chemical modifications to enhance stability, cellular uptake, and binding affinity. These molecules are designed to selectively bind target messenger RNA (mRNA) and inhibit gene expression through mechanisms such as RNase H-mediated degradation or translational blockade. A particularly attractive target for antibacterial intervention is the thiamine pyrophosphate (TPP) regulatory system, which controls essential metabolic pathways in bacteria via TPP riboswitches located in mRNAs. By binding to TPP-regulated mRNAs, chimeric antisense oligonucleotides can disrupt critical gene expression processes, thereby inhibiting bacterial growth and survival.