Antibiotic Cycling Affects Resistance Evolution Independently of Collateral Sensitivity

Area of Science:

• Microbiology
• Evolutionary Biology
• Antimicrobial Resistance

Background:

• Antibiotic cycling is a strategy to mitigate antibiotic resistance.
• The roles of collateral sensitivity and evolved genetic background in resistance are not fully understood.
• The impact of antibiotic exposure patterns on drug cycling outcomes is unknown.

Purpose of the Study:

• To systematically assess the contribution of the evolved genetic background to resistance evolution during antibiotic cycling.
• To investigate the influence of antibiotic exposure patterns on resistance evolution.
• To differentiate the effects of collateral sensitivity from other genetic background effects.

Main Methods:

• Focused on the first drug switch in antibiotic cycling using Salmonella Typhimurium, with cefotaxime as the first antibiotic.
• Normalized antibiotic concentrations to isolate effects beyond collateral sensitivity.
• Varied the second antibiotic and the exposure gradient strength of cefotaxime.

Main Results:

• The evolved genetic background significantly impacts resistance evolution, independent of collateral sensitivity, either enhancing or reducing adaptive potential.
• Antibiotic exposure gradient strength influenced both cefotaxime resistance and adaptation to subsequent antibiotics.
• Weaker cefotaxime gradients led to increased clonal interference and reduced cost of resistance.

Conclusions:

• Antibiotic cycling's effect on resistance evolution is partly independent of collateral sensitivity.
• The evolved genetic background and specific antibiotic combinations play crucial roles in resistance dynamics.
• Antibiotic exposure patterns critically modulate the effectiveness of drug cycling strategies against bacterial resistance.