Sequential antibiotic exposure restores antibiotic susceptibility

Area of Science:

• Microbiology
• Evolutionary Biology
• Pharmacology

Background:

• Antibiotic resistance is a growing global health threat.
• Pairwise cyclic antibiotic therapy shows promise in limiting resistance evolution.
• The impact of resistance evolving to one drug in a cycle needs further investigation.

Purpose of the Study:

• To evaluate the resilience of cyclic antibiotic therapies.
• To understand the mechanisms of resistance evolution and resensitization.
• To identify strategies for improving the longevity of cyclic drug protocols.

Main Methods:

• Conducted over 450 evolution experiments using soft agar gradients and flat plates.
• Identified resistance trade-offs resilient to compensatory mitigation.
• Utilized antimicrobial susceptibility assays, genomic, and phenotypic analyses to detect resensitization and elucidate mechanisms.

Main Results:

• Resistance evolves readily, and collateral sensitivity (CS) does not prevent multidrug resistance or promote resensitization.
• Backward CS, where resistance to drug B increases susceptibility to drug A, can reduce or reverse resistance to drug A.
• Observed reversal of polymyxin B resistance by tigecycline exposure in Escherichia coli due to compensatory mutations.

Conclusions:

• Leveraging backward CS can significantly improve the longevity of drug cycling protocols.
• Backward CS offers a novel strategy to resensitize cells as antibiotic resistance evolves.
• This approach holds potential for more effective antimicrobial treatment strategies.