Therapeutic applications of nucleic acid aptamers in microbial infections

Abstract

Today, the treatment of bacterial infections is a major challenge, due to growing rate of multidrug-resistant bacteria, complication of treatment and increased healthcare costs. Moreover, new treatments for bacterial infections are limited. Oligonucleotide aptamers are single stranded DNAs or RNAs with target-selective high-affinity feature, which considered as nucleic acid-based affinity ligands, replacing monoclonal antibodies. The aptamer-based systems have been found to be talented tools in the treatment of microbial infections, regarding their promising anti-biofilm and antimicrobial activities; they can reduce or inhibit the effects of bacterial toxins, and inhibit pathogen invasion to immune cell, as well as they can be used in drug delivery systems. The focus of this review is on the therapeutic applications of aptamers in infections. In this regard, an introduction of infections and related challenges were presented, first. Then, aptamer definition and selection, with a brief history of aptamers development against various pathogens and toxins were reviewed. Diverse strategies of aptamer application in drug delivery, as well as, the effect of aptamers on the immune system, as the main natural agents of human defense against pathogens, were also discussed. Finally, the future trends in clinical applications of this technology were discussed.

Keywords: Antibiotic resistance; Aptamer; Biofilm; Drug delivery; SELEX; Single stranded DNA or RNA.

Fig. 1

Schematic presentation of DNA aptamer selection using SELEX method

Fig. 2

schematic presentation of aptamer effect as an anti-biofilm agent. Aptamer has led to an early stage suppression of biofilm formation. In the absence of aptamer, flagella-mediated motility results in the formation of mature biofilms

Fig. 3

Schematic presentation of aptamer function against different microbial toxins. A) After binding and oligomerization, in the way to create a pore, toxin heptamer inserts into the target cell and leading to cell lysis. In the presence of aptamer, after binding and oligomerization, pore formation does not occur, which inhibit cell lysis. B) *APC: Antigen presenting cell and **SE: Staphylococcal Enterotoxins. SE bound to MHC class II and TCR is expressed on CD⁴⁺ T cells. MHC class II, SEs and TCR interactions may result in hyper activation of the T cells, leading to the excessive proliferation of T cells and the uncontrolled burst of numerous pro inflammatory cytokines and chemokines. Aptamer inhibits T-cell activation, Therefore, the production of cytokines does not occur. C) PA (protective antigen) binds to the Anthrax Toxin Receptor that then interacts with LF to form the lethal toxin. Translocation of LF through the PA heptamer channel into the host cell cytosol results in cell death. Aptamers block the active site of LF and lead to cell survival. D) BONT (botulinum) is internalized into endosomes. In cytosol, proteolysis by the light chain cleavages SNARE proteins (synaptobrevin, SNAP25 and syntaxin) in the neurons and prevents release of the acetylcholine. Aptamers were bounded to light chain of toxin and caused a strong inhibition of endopeptidase activity

Fig. 4

Schematic presentation of the therapeutic applications of aptamers for microbial infections

Fig. 5

Schematic presentation of aptamer effect as an inhibitor of immune cell invasion A) The aptamer binding to MTB leads to the inhibition of virulent MTB invasion to macrophages. B) The aptamer with S.typhi leads to the entrance inhibition of bacteria into human monocytic cells.