Silencing Antibiotic Resistance with Antisense Oligonucleotides

Abstract

Antisense technologies consist of the utilization of oligonucleotides or oligonucleotide analogs to interfere with undesirable biological processes, commonly through inhibition of expression of selected genes. This field holds a lot of promise for the treatment of a very diverse group of diseases including viral and bacterial infections, genetic disorders, and cancer. To date, drugs approved for utilization in clinics or in clinical trials target diseases other than bacterial infections. Although several groups and companies are working on different strategies, the application of antisense technologies to prokaryotes still lags with respect to those that target other human diseases. In those cases where the focus is on bacterial pathogens, a subset of the research is dedicated to produce antisense compounds that silence or reduce expression of antibiotic resistance genes. Therefore, these compounds will be adjuvants administered with the antibiotic to which they reduce resistance levels. A varied group of oligonucleotide analogs like phosphorothioate or phosphorodiamidate morpholino residues, as well as peptide nucleic acids, locked nucleic acids and bridge nucleic acids, the latter two in gapmer configuration, have been utilized to reduce resistance levels. The major mechanisms of inhibition include eliciting cleavage of the target mRNA by the host’s RNase H or RNase P, and steric hindrance. The different approaches targeting resistance to β-lactams include carbapenems, aminoglycosides, chloramphenicol, macrolides, and fluoroquinolones. The purpose of this short review is to summarize the attempts to develop antisense compounds that inhibit expression of resistance to antibiotics.

Bacterial Nosocomial Infections: Multidrug Resistance as a Trigger for the Development of Novel Antimicrobials

“…The first step to make this therapy clinically possible is to chemically modify the ASOs. The modification of ASOs sugar, backbone, nucleobase, and 3′- and 5′-terminal can improve their stability, avoid nucleases attacks, and preserve target specificity [ 150 ]. ASOs modifications are mainly four: phosphorothioates (PS) linkages, locked (bridged) nucleic acids (LNA/BNA), peptide nucleic acids (PNA), and phosphorodiamidate morpholino oligomers (PMO) [ 148 ].…”

The Role of Staphylococcus aureus YycFG in Gene Regulation, Biofilm Organization and Drug Resistance

“…Our previous study showed that promoter regions of the RNase III–encoding gene ( rnc ) bound and were directly regulated by the YycF ortholog gene VicR in S. mutans [ 82 ]. Antisense regulation mechanisms were used to inhibit antibiotic resistance in bacterial infections using antisense oligonucleotides [ 83 ]. Notably, an endogenous antisense RNA base paired with yycF mRNA was identified in S. aureus [ 84 ], which belongs to a trans-encoded sRNA [ 79 ].…”

Application of Polymeric Nanocarriers for Enhancing the Bioavailability of Antibiotics at the Target Site and Overcoming Antimicrobial Resistance

“…Similarly, antimicrobial gene therapies, such as antisense strategy [26], transcription factor decoys [27], or CRISPR-Cas systems [28], have recently attracted enormous attention and opened new avenues to overcome multidrug resistance and restore antibiotic susceptibility. However, their therapeutic potential requires an efficient mechanism of entry of the gene agents into the bacterial cell, which is inherently a hurdle because of their poor stability, rapid clearance in blood circulation, and lack of targeting ability.…”