Investigation of mRNA-based antibiotics

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3K, (RXR)4XB, Tat, Dap9). Credit : Nucleic acid research (2022). DOI: 10.1093/nar/gkac362″ width=”800″ height=”399″/>

Schematic illustration of the applied PNA technology and the PNA target region of the conserved essential gene, acpP. (A) An antisense PNA is coupled to a CPP to facilitate intrabacterial delivery. When targeting essential bacterial genes, CPP-PNA conjugates can serve as potent antimicrobial molecules. Parts of this image were created with Smart (Servier medical art). (B) Multiple sequence alignment (created with http://multalin.toulouse.inra.fr/multalin/; (118)) of the essential acpP gene including the following γ-proteobacteria: UPEC 536 (CP000247.1), E. coli CFT073 (CP051263.1), E. coli K-12 (CP032667.1), Shigella dysenteriae (CP000034.1), Citrobacter rodentium (CP038008.1), Salmonella enterica subsp. enterica serotype Typhimurium str. LT2 (AE006468.2), Salmonella enterica subsp. enterica serotype Typhimurium str. SL1344 (FQ312003.1), Klebsiella pneumoniae (CP003200.1) and Yersinia pestis (NC_003143.1). A defined section (–40 to +90 nt) including the region around the PNA binding site (gray box) is shown. The following color code was applied: perfect consensus black, cyan variable alignment columns (nucleotide substitution green). (C) Relevant region of acpP mRNA in UPEC 536, with the PNA target sequence shaded in green. The initiation codon (AUG) is shown in bold. Below, the PNA sequence is represented (green box) with the different CPPs conjugated for delivery in UPEC ((KFF)3K, (RXR)4XB, Tat, Dap9). Credit: Nucleic acid research (2022). DOI: 10.1093/nar/gkac362

In the fight against the COVID-19 pandemic, mRNA-based vaccines have impressively demonstrated their potential. Using this technology, scientists have been able to rapidly develop and bring to market SARS-CoV-2 vaccines that have been extremely effective in protecting millions of people from severe disease progression of COVID-19 or even dead.

However, RNA-based medicine can be used to fight more than just viruses. Among others, it can also be considered as a candidate for a new type of antibiotics which can be used to treat bacterial infections in a suitable way.

Which prerequisites these active agents have to fulfill and how they work in the bacterium – this was investigated by researchers at the University of Würzburg (JMU). Teams from the Institute for Molecular Biology of Infections (IMIB) and the Helmholtz Institute for RNA-Based Infection Research (HIRI) were involved. They present the results of their work in the current issue of Nucleic acid research.

Traditional antibiotics are increasingly failing

“The number of bacterial strains resistant to antibiotics is increasing worldwide; treatments with conventional active agents are increasingly failing. We therefore urgently need new drugs to combat these pathogens in a targeted and effective way”, says the Professor Jörg Vogel. Vogel is Chair of Molecular Biology of Infections I at JMU and Director of HIRI as well as the corresponding author of this study.

Programmable mRNA antibiotics could be the solution to this problem. The strategy is simple: “We introduce short chains of bases into bacteria designed to match specific genes exactly,” Vogel explains. When these fragments bind to the corresponding mRNA of the gene of interest, they cancel the production of proteins and, ideally, the bacterium dies.

Extinguished by the mirror image

In science, this approach is known as “antisense technology.” The structure of these assets is a mirror image of a gene, allowing them to block it effectively. The first drugs that work according to this principle are already on the market, such as those for the treatment of the consequences of spinal muscular atrophy or hepatitis C. However, mRNA-based antibiotics have so far been confined to the laboratory.

In their study, the Würzburg scientists focused on bacterial strains of the uropathogenic Escherichia coli (UPEC) type. In the vast majority of cases, these bacteria cause a urinary tract infection in about every second woman once in her lifetime. The excessive use of antibiotics in recent decades has led to the development of resistance to current therapies in many of these bacteria, particularly complicating the treatment of frequent recurrent urinary tract infections.

Answers to three key questions

The research teams involved aimed to answer three central questions. First: Are the designed active agents (in particular, antisense peptide nucleic acids that target mRNAs of essential bacterial genes) specific? In other words, do they actually block a single specific bacterial gene? Or do they also affect other mRNAs? The answer is clear: “Our results show that the applied base pairs only block the gene of interest,” says Vogel.

Second: How does the bacterium react to the translocation of these RNA antibiotics into the cell? Answer: Bacteria show a stress response, and therefore, unfortunately, not as expected. This is mainly due to the fact that antisense peptide nucleic acids are relatively large in size. Stress therefore mainly occurs when these biomolecules cross the bacterial membrane.

However, there is good news regarding the answer to question three: is it possible to reduce the size of these “base pair extracts”? Yes it is. “So far, scientists have assumed that between nine and 14 base pairs are needed to prevent non-specific binding to other genes,” says Vogel. Published results now show that nine base pairs are sufficient; thus, extracts can be kept relatively small.

Overall, according to the study authors, the results show that mRNA-based antibiotics are in principle suitable for combating uropathogenic strains of Escherichia coli. However, several important questions still need to be addressed before using this approach in clinics. Yet there is an urgent need: “If we don’t want to see antibiotic-resistant microbes thwart the successes of modern medicine, we need new tools that facilitate the targeted treatment of pathogens,” says Jörg Vogel.


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More information:
Linda Popella et al, Comprehensive review of PNA-based antisense antibiotics targeting various essential genes in uropathogenic Escherichia coli, Nucleic acid research (2022). DOI: 10.1093/nar/gkac362

Provided by Julius-Maximilians-Universität Würzburg


Quote: Survey of mRNA-based antibiotics (2022, June 28) Retrieved June 28, 2022 from https://medicalxpress.com/news/2022-06-mrna-based-antibiotics.html

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