Nonoptimal Gene Expression Creates Latent Potential for Antibiotic Resistance

Area of Science:

• Microbiology
• Genetics
• Evolutionary Biology

Background:

• Bacteria possess gene regulatory mechanisms to survive antibiotic stress.
• Suboptimal gene regulation under antibiotic pressure can lead to mutations conferring antibiotic resistance.
• The extent of non-optimal gene regulation and its quantitative impact on resistance across different antibiotics remain unclear.

Purpose of the Study:

• To investigate the quantitative relationship between fitness, gene expression, and antibiotic potency.
• To determine how changes in specific gene expression impact antibiotic resistance.
• To understand the degree to which natural gene regulation is suboptimal for distinct antibiotics.

Main Methods:

• Developed a pooled-strain drug-diffusion assay.
• Screened Escherichia coli overexpression and knockout libraries against 31 antibiotics.
• Synthetically controlled the expression of single-drug and multidrug resistance genes.

Main Results:

• Identified a diverse set of genes whose altered expression confers antibiotic resistance in a drug-specific manner.
• Observed significant changes in fitness-expression functions of resistance genes under antibiotic treatment.
• Discovered a log-sensitivity relation governing fitness-expression dynamics.

Conclusions:

• A simple quantitative relation exists between fitness, gene expression, and antibiotic potency.
• Many genes are expressed non-optimally under antibiotic treatment, providing avenues for resistance.
• Regulatory mutations altering gene expression can activate latent defenses and contribute to antibiotic resistance.