Antibacterial antisense.

Abstract

The concept of using antisense antibiotics is revolutionary. Instead of targeting proteins or macromolecular complexes, as do traditional antibiotics, antisense oligomers target specific genes, rRNA or mRNA, and inhibit expression of the targeted sequence. Recent advances have shown that two types of antisense oligomer, peptide nucleic acids and phosphorodiamidate morpholino oligomers (PMOs), inhibit gene expression in a sequence-specific and dose-dependent manner at low micromolar concentrations. Cellular uptake has been improved by shortening the length of the antisense oligomer and/or attaching membrane-permeating peptides. In addition to Escherichia coli, other bacteria such as Staphylococcus aureus and Mycobacterium tuberculosis are susceptible to antisense antibiotics. The first animal studies demonstrated that PMOs reduced E. coli approximately 10-fold in mouse peritonitis infections. Non-therapeutic uses of bacterial antisense are providing novel tools to identify new targets, elucidate mechanisms of antibiotic action and design new antibiotics. Gene-specific antisense antibiotics now appear possible, and additional preclinical animal studies should move this technology towards that goal.