Collateral sensitivity constrains resistance evolution of the CTX-M-15 β-lactamase

Area of Science:

• Microbiology
• Pharmacology
• Genetics

Background:

• Antibiotic resistance poses a significant global health threat.
• The discovery of novel antibiotics is insufficient to meet the growing challenge.
• New strategies are essential for effective bacterial infection treatment.

Purpose of the Study:

• To investigate collateral sensitivity patterns in extended-spectrum β-lactamase (ESBL) CTX-M-15.
• To identify mutations conferring resistance to certain antibiotics while increasing susceptibility to others.
• To evaluate the efficacy of drug combinations in combating antibiotic resistance.

Main Methods:

• Analysis of collateral sensitivity patterns for CTX-M-15.
• Identification of non-synonymous mutations conferring resistance/susceptibility.
• In vitro and in vivo (mice) testing of antibiotic combinations.

Main Results:

• Three mutations were identified that increase resistance to mecillinam or piperacillin-tazobactam.
• These mutations simultaneously conferred full susceptibility to several cephalosporin drugs.
• A combination of mecillinam and cefotaxime effectively eliminated both wild-type and resistant CTX-M-15 in vitro and in mice.

Conclusions:

• Mecillinam and cefotaxime combination therapy constrains the resistance evolution of CTX-M-15.
• Drug combinations can be rationally designed to limit resistance evolution in horizontally transferred genes.
• Exploiting collateral sensitivity is a promising strategy for developing new antibiotic treatments.