How bacteria develop resistance to antisense antibiotics - and how future therapies can be designed to reduce the risk of resistance
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 classical antibiotics fail. A team of researchers from TWINCORE, Centre for Experimental and Clinical Infection Research, the RESIST Cluster of Excellence and from the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg has now studied, how bacteria adapt to asobiotics. They recently published their finding in Nature Communications.
Asobiotics are based on short sequence 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 used laboratory evolution experiments in four major Gram-negative bacterial pathogens to systematically investigate how resistance to asobiotics emerges”, says Adam Mulkern, a former postdoctoral researcher in the group “Systems Biology of Microbial Communities” at TWINCORE and first author of the study. “We found that bacteria either prevent the antibiotic from entering the cell or alter the cellular response once the molecule reaches its target.” Importantly, which resistance mechanism evolves depends largely on the peptide used to deliver the antibiotic into the bacterial cell.
In additional control evolution experiments using non-targeting ("scrambled") antisense molecules demonstrated the scientists could show that the observed mutations were specifically driven by antisense activity. The researchers also confirmed that a single mutation in the gene prfB is sufficient to increase resistance, validating a previously unknown resistance mechanism.
"Our work shows that the delivery system is not just a carrier, it is a critical design feature that determines how readily resistance evolves," says TWINCORE group leader and senior author Marco Galardini. "Choosing delivery mechanisms that are less prone to resistance could significantly improve the long-term effectiveness of programmable antibiotics."
The study was carried out at TWINCORE within the Cluster of Excellence RESIST in collaboration with colleagues at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg, under the supervision of its director Jörg Vogel. The findings provide an important framework for developing programmable antibiotics that are better equipped to keep pace with bacterial evolution and help address the growing global threat of antimicrobial resistance.
Adam J. Mulkern, Thu-Hien Vu, Linda Popella, Tobias Kerrinnes, Svetlana Ðurica-Mitić, Manuel Halte, Kylee Dresbach-Hill, Anne-Catrin Uhlemann, Stephan Uphoff, Lars Barquist, Jörg Vogel & Marco Galardini
Nature Communications volume 17, Article number: 8262 (2026)
Postdoctoral Researcher
Mulkern A, Vu T, Popella L, Kerrinnes T, Ðurica-Mitić S, Halte M, Dresbach-Hill K, Uhlemann A, Uphoff S, Barquist L, Vogel J, Galardini M
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