Predictable Phenotypes of Antibiotic Resistance Mutations.

Area of Science:

• Microbiology
• Evolutionary Biology
• Genetics

Background:

• Antibiotic-resistant bacteria pose a significant global health threat.
• Predicting the evolutionary trajectory of resistance mutations is crucial for effective treatment strategies.
• Epistatic interactions between resistance mutations may complicate predictions of their stability.

Purpose of the Study:

• To investigate epistatic interactions between chromosomal antibiotic resistance mutations.
• To determine how strain background and genetic distance influence resistance and fitness phenotypes.
• To assess the predictability of combined resistance mutation effects.

Main Methods:

• Analysis of 13 chromosomal resistance mutations across 10 host strains of *Salmonella enterica* and *Escherichia coli*.
• Systematic screening for epistatic interactions between multiple resistance mutations.
• Evaluation of strain-independent phenotypes for various resistance mutations.

Main Results:

• Epistatic interactions between antibiotic resistance mutations were found to be rare.
• The combined effects of multiple resistance mutations on resistance and fitness were largely predictable.
• Most resistance mutations, particularly target alteration mutations, exhibited strain-independent phenotypes across species.
• A few outlier mutations demonstrated significant strain-specific effects.

Conclusions:

• Antibiotic resistance mutation interactions are generally predictable, simplifying evolutionary forecasting.
• Strain background has a limited but sometimes critical impact on resistance mutation phenotypes.
• Understanding these predictable interactions aids in combating the spread of antibiotic resistance.