Antibiotic collateral sensitivity is contingent on the repeatability of evolution.

Area of Science:

• Microbiology
• Evolutionary Biology
• Computational Biology

Background:

• Antibiotic resistance is a critical global health threat requiring novel therapeutic strategies.
• Collateral sensitivity, where resistance to one drug increases susceptibility to another, is a promising avenue.
• In vitro evolution studies may overestimate the benefits of sequential drug regimens.

Purpose of the Study:

• To investigate the reliability of collateral sensitivity predictions from in vitro evolution.
• To quantify the probability of cross-resistance versus collateral sensitivity in sequential drug treatments.
• To understand the genetic basis for differential drug responses after sequential exposure.

Main Methods:

• Mathematical modeling using combinatorially complete fitness landscapes for Escherichia coli.
• Experimental evolution to test sequential drug regimens.
• Targeted and whole genome sequencing to identify genetic divergence.

Main Results:

• Sequential drug regimens can lead to unexpected cross-resistance, contradicting collateral sensitivity predictions.
• Experimental evolution confirmed that a second drug can elicit either increased susceptibility or resistance.
• Genetic divergence was identified as the key factor driving these differential responses.

Conclusions:

• The therapeutic success of evolutionarily-informed strategies depends on understanding the probabilistic nature of drug resistance evolution.
• Accurate prediction of drug response requires accounting for stochastic genetic changes.
• Rigorous assessment of fitness landscapes is crucial for designing effective sequential antibiotic therapies.