Facile accelerated specific therapeutic (FAST) platform develops antisense therapies to counter multidrug-resistant bacteria

Eller, Kristen A.; Aunins, Thomas R.; Courtney, Colleen M.; Campos, Jocelyn K.; Otoupal, Peter B.; Erickson, Keesha E.; Madinger, Nancy; Chatterjee, Anushree

doi:10.1038/s42003-021-01856-1

Cited by 21 publications

(40 citation statements)

References 69 publications

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“…This methodology is not only rapid, but it results in highly specific antisense sequences. The authors utilized the platform to design antisense compounds that act as antibiotics against five multidrug resistant Enterobacteriaceae clinical isolates and an antisense compound that modifies the action of carbapenem against a carbapenem-resistant E. coli strain [95,96]. In the latter case, the target genes were selected following a novel approach.…”

Section: Steric Hindrancementioning

confidence: 99%

Silencing Antibiotic Resistance with Antisense Oligonucleotides

2021

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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.

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Section: Steric Hindrancementioning

confidence: 99%

Silencing Antibiotic Resistance with Antisense Oligonucleotides

2021

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“…Bioinformatics is also bringing a boost for antisense therapies, with the facile accelerated specific therapeutic (FAST) platform being the most recent platform to develop antisense therapies to combat MDR bacteria [ 164 ]. Aunins et al used FAST to create PNAs against CRE bacterial genes identified by transcriptomics.…”

Section: Antimicrobial Alternatives Under Investigationmentioning

confidence: 99%

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

et al. 2021

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Nosocomial bacterial infections are associated with high morbidity and mortality, posing a huge burden to healthcare systems worldwide. The ongoing COVID-19 pandemic, with the raised hospitalization of patients and the increased use of antimicrobial agents, boosted the emergence of difficult-to-treat multidrug-resistant (MDR) bacteria in hospital settings. Therefore, current available antibiotic treatments often have limited or no efficacy against nosocomial bacterial infections, and novel therapeutic approaches need to be considered. In this review, we analyze current antibacterial alternatives under investigation, focusing on metal-based complexes, antimicrobial peptides, and antisense antimicrobial therapeutics. The association of new compounds with older, commercially available antibiotics and the repurposing of existing drugs are also revised in this work.

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“…The link between miR-2392 and COVID-19 infection prompted the develop of an effective antiviral approach for COVID-19 by inhibiting miR-2392. We used the Nanoligomer platform to develop an effective antisense-based therapeutic against human miR-2392 (Eller et al, 2021), termed SBCov207 (Fig. 6A).…”

Section: Inhibiting Mir-2392: a Novel Antiviral Covid-19 Therapeuticmentioning

confidence: 99%

The Great Deceiver: miR-2392’s Hidden Role in Driving SARS-CoV-2 Infection

McDonald

Enguita

Taylor

et al. 2021

Preprint

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SummaryMicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a circulating miRNA, miR-2392, that is directly involved with SARS-CoV-2 machinery during host infection. Specifically, we found that miR-2392 was key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia as well as promoting many symptoms associated with COVID-19 infection. We demonstrate miR-2392 is present in the blood and urine of COVID-19 patients tested, but not detected in COVID-19 negative patients. These findings indicate the potential for developing a novel, minimally invasive, COVID-19 detection method. Lastly, using both in vitro human and in vivo hamster models, we have developed a novel miRNA-based antiviral therapeutic targeting miR-2392 that significantly reduces SARS-CoV-2 viability and may potentially inhibit a COVID-19 disease state in the host.

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Facile accelerated specific therapeutic (FAST) platform develops antisense therapies to counter multidrug-resistant bacteria

Cited by 21 publications

References 69 publications

Silencing Antibiotic Resistance with Antisense Oligonucleotides

Silencing Antibiotic Resistance with Antisense Oligonucleotides

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

The Great Deceiver: miR-2392’s Hidden Role in Driving SARS-CoV-2 Infection

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