Forecasting Multitrait Resistance Evolution under Antibiotic Stress

Area of Science:

• Microbiology
• Evolutionary Biology
• Computational Biology

Background:

• Bacteria utilize efflux pumps to survive antibiotic stress.
• Mutations in efflux pump genes or regulators increase pump expression, leading to antibiotic resistance.
• Complex regulatory networks make experimental mapping of these mutations challenging.

Purpose of the Study:

• To develop a mathematical framework for predicting mutation spectra in bacterial efflux pump regulation.
• To simulate in silico evolution of Pseudomonas aeruginosa under antibiotic pressure.
• To understand how regulatory networks and shared protein use shape resistance evolution.

Main Methods:

• Developed a mathematical framework integrating dynamical equations for efflux pump regulation.
• Employed a genetic algorithm for parameter estimation and evolutionary simulations.
• Simulated in silico evolution of Pseudomonas aeruginosa exposed to meropenem, tobramycin, and ciprofloxacin.

Main Results:

• Identified mutational spectra affecting four RND efflux pumps and their shared regulatory network in Pseudomonas aeruginosa.
• Found that single-target regulators were the most frequently mutated genes, aligning with clinical observations.
• Demonstrated that shared protein use (OprM) influences distinct mutational patterns and that mutations can lead to collateral sensitivity or cross-resistance.
• Observed that efflux pump genes are lost in the absence of antibiotics, suggesting a potential strategy to reduce resistance evolution.

Conclusions:

• The mathematical framework accurately predicts mutation spectra and evolutionary trajectories of bacterial efflux pumps.
• Shared regulatory components and protein use significantly impact resistance evolution.
• Bacterial evolution under antibiotic pressure can lead to complex phenotypes, including collateral sensitivity and cross-resistance.
• Antibiotic withdrawal may be a viable strategy to decrease the bacterial capacity for evolving resistance.