Antisense oligonucleotides: design, implementation and future perspectives in microbiology

Advances in molecular biology have expanded antimicrobial strategies that traditionally targeted proteins or metabolic pathways to now include RNA, enabling a previously unattainable precision through control of gene expression. The clinical potential of RNA-therapeutics was demonstrated during the COVID-19 pandemic, when mRNA vaccines marked a transformative milestone for RNA-based interventions for viral infections. Increasingly, similar principles are emerging for the treatment of bacterial infections. Antisense oligonucleotides (ASOs) bind complementary mRNA sequences to induce RNase H-mediated degradation or block their translation. Initially developed for genetic and neurodegenerative disorders, ASOs are now emerging as next-generation antibacterials, termed ASOBiotics, designed to silence essential bacterial genes. In this review, we explore the advances of ASO technologies with applications in bacterial pathogens, outlining design considerations while discussing the challenges and opportunities for making precision antibacterial therapeutics.