Antisense antimicrobial therapeutics

Abstract

Antisense antimicrobial therapeutics are synthetic oligomers that silence expression of specific genes. This specificity confers an advantage over broad-spectrum antibiotics by avoiding unintended effects on commensal bacteria. The sequence-specificity and short length of antisense antimicrobials also pose little risk to human gene expression. Because antisense antimicrobials are a platform technology, they can be rapidly designed and synthesized to target almost any microbe. This reduces drug discovery time, and provides flexibility and a rational approach to drug development. Recent work has shown that antisense technology has the potential to address the antibiotic-resistance crisis, since resistance mechanisms for standard antibiotics apparently have no effect on antisense antimicrobials. Here, we describe current reports of antisense antimicrobials targeted against viruses, parasites, and bacteria.

Figure 1

Chemical structures of antisense oligomers. Five commonly used antisense oligomers include phosphorothioates (S-DNA), locked nucleic acids (LNA), peptide nucleic acids (PNA), phosphorodiamidate morpholino-oligomers (PMO), and bridged nucleic acids (BNA).

Figure 2

Mechanisms of antisense oligomer inhibition of gene expression. (a) The antisense oligomer binds to the target complementary mRNA, sterically blocking the 30S ribosomal subunit and initiation of translation. (b) RNase H is activated upon oligomer binding, leading to the degradation of the targeted mRNA.