How bacteria develop resistance to programmable antibiotics

Antimicrobial resistance represents a significant obstacle for contemporary healthcare. A novel category of programmable antibiotics, termed asobiotics, can counteract bacterial infections when traditional antibiotics prove ineffective. In a recent study published in Nature Communications, researchers from TWINCORE, the RESIST Cluster of Excellence, and the Helmholtz Institute for RNA-based Infection Research investigated how bacteria develop resistance to asobiotics.

Asobiotics utilize short antisense oligonucleotide sequences to selectively inhibit crucial bacterial genes, with sequences that can be swiftly altered to combat evolving antibiotic-resistant pathogens.

The researchers conducted laboratory evolution experiments across four major Gram-negative bacterial pathogens, examining the emergence of resistance mechanisms. Adam Mulkern, a former postdoctoral researcher in the Systems Biology of Microbial Communities group at TWINCORE and the study's first author, elucidated that bacteria either inhibit the antibiotic's cellular entry or modify the cellular response following its target engagement.

Crucially, the type of resistance mechanism that develops hinges largely on the peptide employed to deliver the antibiotic into the bacterial cell.

Control experiments using non-targeting antisense molecules revealed that the observed mutations were specifically driven by the antibiotic's antisense activity. Furthermore, the team confirmed that a single mutation in the prfB gene was sufficient to bolster resistance, validating an overlooked resistance mechanism. Marco Galardini, the TWINCORE group leader and senior author of the study, emphasized that the delivery system is not merely a transporter; it is a pivotal design element that influences how readily resistance evolves.

By selecting delivery mechanisms less susceptible to resistance, the long-term efficacy of programmable antibiotics could be markedly enhanced.

These findings offer a vital framework for the development of programmable antibiotics that can more effectively adapt to bacterial evolution, addressing the escalating global challenge of antimicrobial resistance.