Staying One Step Ahead of the Development of Resistance
How Bacteria Develop Resistance to Antisense Antibiotics—and How Future Therapies Can Be Made Less Susceptible to It
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Antimicrobial resistance is one of the greatest challenges facing modern medicine. A new class of programmable antibiotics, known as “asobiotics,” can be used to treat bacterial infections when conventional antibiotics fail. A research team from TWINCORE, the Center for Experimental and Clinical Infection Research; the RESIST Cluster of Excellence; and the Helmholtz Institute for RNA-Based Infection Research (HIRI) in Würzburg has now investigated how bacteria adapt to asobiotics. They recently published their findings in *Nature Communications*.
Asobiotics are based on short sequences of antisense oligonucleotides that selectively block essential bacterial genes. Because their sequence can be rapidly redesigned, they offer the potential to keep pace with the evolution of antibiotic-resistant pathogens.
“We conducted evolutionary experiments in the lab on four major Gram-negative bacterial pathogens to systematically investigate how resistance to asobiotics develops,” says Adam Mulkern, a former postdoctoral researcher in the “Systems Biology of Microbial Communities” group at TWINCORE and first author of the study. “We found that bacteria either prevent the antibiotic from entering the cell or alter the cellular defense response once the molecule has reached its target.” Importantly, the resistance mechanism that develops depends largely on the peptide used to deliver the antibiotic into the bacterial cell.
In additional control evolution experiments using non-targeted (“scrambled”) antisense molecules, the scientists were able to show that the observed mutations were specifically triggered by the antisense activity. The researchers also confirmed that a single mutation in the prfB gene is sufficient to increase resistance, thereby validating a previously unknown resistance mechanism.
“Our work shows that the transport system is not merely a carrier but a crucial structural feature that determines how easily resistance develops,” says TWINCORE group leader and senior author Marco Galardini. “Choosing transport systems that are less susceptible to resistance could significantly improve the long-term efficacy of programmable antibiotics.”
The study was conducted at TWINCORE as part of the RESIST Cluster of Excellence in collaboration with colleagues at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg, led by its director, Jörg Vogel. The findings provide an important framework for the development of programmable antibiotics that are better able to keep pace with bacterial evolution and help counter the growing global threat of antibiotic resistance.
Note: This article has been translated using a computer system without human intervention. LUMITOS offers these automatic translations to present a wider range of current news. Since this article has been translated with automatic translation, it is possible that it contains errors in vocabulary, syntax or grammar. The original article in German can be found here.
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