Large scale laboratory evolution uncovers clinically relevant collateral antibiotic sensitivity

Area of Science:

• Microbiology
• Evolutionary Biology
• Pharmacology

Background:

• Antibiotic resistance is a growing global health threat.
• Collateral sensitivity (CS) sequential therapies are a promising strategy to mitigate resistance evolution.
• The repeatability and clinical relevance of CS interactions require further investigation.

Purpose of the Study:

• To assess the evolutionary repeatability of CS interactions under different laboratory adaptive evolution (ALE) conditions.
• To identify novel CS relationships with potential clinical applications.
• To determine the predictive power of different ALE platforms for clinical CS effects.

Main Methods:

• Evolving multiple lineages of E. coli against tigecycline (TIG) and piperacillin (PIP) using three distinct ALE platforms.
• Generating over 130 resistant mutants and performing 540 resistance and CS measurements.
• Analyzing a clinical dataset of over 750 multidrug-resistant (MDR) E. coli isolates.

Main Results:

• A highly repeatable CS relationship between TIG and polymyxin B (POL) was identified across all ALE platforms.
• The mechanism involves TIG resistance leading to Lon protease deactivation and exopolysaccharide overproduction, causing hypersensitivity to POL.
• The soft agar gradient evolution (SAGE) platform demonstrated the best prediction of clinical collateral effects.

Conclusions:

• The identified TIG-POL CS interaction is robust and preserved across different evolutionary microenvironments.
• This CS relationship is present in clinical uropathogenic MDR E. coli isolates.
• A framework for identifying clinically relevant and robust CS interactions is established, aiding in the development of strategies to combat antibiotic resistance.