Alternative Evolutionary Paths to Bacterial Antibiotic Resistance Cause Distinct Collateral Effects

Area of Science:

• Microbiology
• Evolutionary Biology
• Genetics

Background:

• Antibiotic resistance is a growing global health threat.
• Collateral sensitivity, where resistance to one drug increases sensitivity to another, is a potential strategy to combat resistance.
• This phenomenon is poorly understood in opportunistic pathogens like Pseudomonas aeruginosa.

Purpose of the Study:

• To investigate collateral sensitivity and resistance patterns in Pseudomonas aeruginosa.
• To explore the genetic basis of these collateral effects.
• To assess the potential of collateral sensitivity for novel antibiotic therapies.

Main Methods:

• Experimentally evolved 160 independent populations of Pseudomonas aeruginosa to high resistance against eight antibiotics.
• Assessed collateral sensitivity and cross-resistance patterns.
• Performed whole-genome sequencing on 81 evolved populations.
• Conducted genomic and functional genetic analysis.

Main Results:

• Pseudomonas aeruginosa rapidly evolved resistance, exhibiting both collateral sensitivity and cross-resistance.
• Collateral effect patterns differed from other bacterial species, indicating interspecific variations.
• Contrasting collateral effects were observed among replicate populations.
• Distinct evolutionary pathways, including mutations in regulatory genes (nalC, mexZ, pmrB), determined collateral outcomes.

Conclusions:

• Collateral sensitivity and cross-resistance vary significantly in Pseudomonas aeruginosa.
• Evolutionary pathways and specific gene mutations underlie these varied collateral effects.
• Understanding these variations is crucial for developing effective antibiotic treatment strategies.