Review Article
Advances in the delivery of antisense oligonucleotides for combating bacterial infectious diseases

https://doi.org/10.1016/j.nano.2017.12.026Get rights and content

Abstract

Discovery and development of new antibacterial drugs against multidrug resistant bacterial strains have become more and more urgent. Antisense oligonucleotides (ASOs) show immense potential to control the spread of resistant microbes due to its high specificity of action, little risk to human gene expression, and easy design and synthesis to target any possible gene. However, efficient delivery of ASOs to their action sites with enough concentration remains a major obstacle, which greatly hampers their clinical application. In this study, we reviewed current progress on delivery strategies of ASOs into bacteria, focused on various non-virus gene vectors, including cell penetrating peptides, lipid nanoparticles, bolaamphiphile-based nanoparticles, DNA nanostructures and Vitamin B12. The current review provided comprehensive understanding and novel perspective for the future application of ASOs in combating bacterial infections.

Section snippets

Advantages of antisense antibacterial agents

Compared with traditional antibiotics, ASOs-based antibacterial agent has many advantages: (1) Easy design: In theory, all the disease-related genes in the clinical pathogenic bacteria can be targeted by ASOs, and the only knowledge necessary for ASO design is the nucleotide sequence. (2) Precise target: ASOs can target their complementary mRNA and selectively prevent the expression of single isoform among a class of closely related genes, which is often difficult to be achieved by traditional

Dilemma of developing antisense antibacterial agents

In spite of remarkable technology progress in the research of RNA-based therapeutics targeting host cells, two main obstacles hinder further development and application of antisense antibacterial agents.

Delivery barriers of antisense antibacterial agents

The successful delivery of ASOs into bacterial cells is much more difficult than into mammalian cells, which has been the key restraint hindering the development of antisense antibacterial agents.49 The reasons behind the difficulty mainly include three aspects:

Current delivery strategies for antisense antibacterial agents

Currently, ASO drugs used in non-infectious diseases, delivered by covalent coupling or non-covalent binding strategy, has made a great breakthrough. However, the development of delivery system for antisense antibacterial agents relatively lags, and most reported data focused on the ASO–cell-penetrating peptide (CPP) conjugation. However, the minimum inhibitory concentrations of ASO–CPP against pathogenic bacteria observed by different labs mostly ranged from 10 to 40 μM, which is much higher

Conclusions

RNA-based therapeutics has made great advancement in the field of cancer, severe and rare genetic disorders, and cardiovascular and metabolic diseases. Several RNA-based drugs discovered by the leading companies, such as Ionis Pharmaceuticals™ and Regulus Therapeutics, Inc., have been researched in clinical phase, which will carry us toward a new stage of antisense antibacterial agents. During the past three decades, the potency of ASOs to inhibit the expression of essential genes, resistant

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    Competing financial interests: All of the authors declared no competing financial interest.

    This work is supported by the National Natural Science Foundation of China (81402975, 81502143, 51675411) and the youth talent cultivation grants of the Fourth Military Medical University.

    1

    These three authors contributed equally to this work.

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