“Recurrent Extinction of Resistance Mutations Leads to Convergent Multidrug Resistance in Sequential Antibiotic Treatment”
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
To overcome the challenge of clinical antibiotic resistance, evolutionary insights should be used to optimize antibiotic treatment strategy. Using an evolution protocol that mimics clinical antibiotic pharmacodynamics by applying strong selection while maintaining population diversity, we evolved Escherichia coli under single or sequential antibiotic exposures until sustained survival emerged. Under single-antibiotic selection, endpoint phenotypes were reproducible, yet replicate populations evolving in parallel often followed divergent genetic trajectories, revealing multiple pathways to resistance, persistence, and tolerance. Remarkably, sequential antibiotic use shifted these paths from divergence to convergence, driven by extinction of resistance mutations when switching to effective antibiotics exhibiting collateral sensitivity. Single-cell RNA sequencing revealed that evolved lineages shifted away from the wild-type state, with fewer cells exhibiting high ribosomal gene counts, a signature consistent with persistence, while also uncovering lineage-specific expression differences that suggest distinct underlying mechanisms. These findings provide evolutionary insights that can inform antibiotic treatment strategies to slow the emergence of multidrug resistance.
