Antisense Antibiotics: A Brief Review of Novel Target Discovery and Delivery

Hui      Bai; Xiaoyan      Xue; Zheng      Hou; Ying      Zhou; Jingru      Meng; Xiaoxing      Luo

Abstract

The nightmare of multi-drug resistant bacteria will still haunt if no panacea is ever found. Efforts on seeking desirable natural products with bactericidal property and screening chemically modified derivatives of traditional antibiotics have lagged behind the emergence of new multi-drug resistant bacteria. The concept of using antisense antibiotics, now as revolutionary as is on threshold has experienced ups and downs in the past decade. In the past five years, however, significant technology advances in the fields of microbial genomics, structural modification of oligonucleotides and efficient delivery system have led to fundamental progress in the research and in vivo application of this paradigm. The wealthy information provided in the microbial genomics era has allowed the identification and/or validation of a number of essential genes that may serve as possible targets for antisense inhibition; antisense oligodeoxynucleotides (ODNs) based on the 3rd generation of modified structures, e.g., peptide nucleic acids (PNAs) and phosphorodiamidate morpholino oligomers (PMOs) have shown great potency in gene expression inhibition in a sequence-specific and dosedependent manner at low micromolar concentrations; and cell penetrating peptide mediated delivery system has enabled the effective display of intracellular antisense inhibition of targeted genes both in vitro and in vivo. The new methods show promise in the discovery of novel gene-specific antisense antibiotics that will be useful in the future battle against drug-resistant bacterial infections. This review describes this promising paradigm, the targets that have been identified and the recent technologies on which it is delivered.

Keywords: Antisense oligonucleotides, antisense antibiotics, antibiotic resistance, oligodeoxynucleotides, (ODNs), morpholino oligomers (PMOs), peptide nucleic acids, (PNAs), phosphorodiamidate morpholino oligomers, (PMOs), Staphylococcus aureus, MRSA, Enterococci, VRE, Mycobacterium tuberculosis, Escherichia coli, Klebsiella pneumonia, Pseudomonades, Acinetobacter, pathogenesis, DNA replication, RNA, PS-ODNs, LNAs, Phos phorothioa te DNA, 2'-O-Methox yethyl RNA, (2'-MOE), 2'-O-methyl RNA, Phosphorodiamidate Morpholino, Thiophosphoramidate, Locked Nucleic Acid, Bicyclic Nucleic Acid, β-lactamase, Enterococcus faecalis, Campylobacter jejun, Bacillus anthracis, Mycobacterium smegmatis, Mycobacterium avium, Entamoeba histolytica, Streptococcus mutans, Burkholderia cepacia, Salmonella enterica serovar Typhimurium, gene therapy, gram-negative bacteria, Antibacterial Therapy, Cell penetrating peptide, Pseudomonas aeruginosa, Bacillus subtilis, Corynebacterium efficiens