Phage Resistance Modulates Escherichia coli B Response to Metal-Based Antimicrobials

Area of Science:

• Microbiology
• Evolutionary Biology
• Genomics

Background:

• Multidrug-resistant bacteria necessitate novel antimicrobial strategies.
• Bacteriophage (phage) therapy and metal-based compounds show promise.
• Evolutionary trade-offs of combined selective pressures are poorly understood.

Purpose of the Study:

• Investigate how prior T4 phage exposure affects *Escherichia coli* adaptation to iron (III) stress.
• Assess phenotypic and genomic signatures of dual resistance.
• Understand the impact of stressor sequence on microbial adaptation.

Main Methods:

• Experimental evolution of *Escherichia coli* B under four conditions: control, T4 phage, iron (III) sulfate, and sequential phage/iron (III).
• Daily passaging for 35 days with ten biological replicates per condition.
• Whole-genome sequencing to identify genetic adaptations.

Main Results:

• Phage resistance evolved rapidly (within 24 h).
• Iron-selected populations developed high iron tolerance but lost resistance to other metals and antibiotics.
• Prior phage exposure maintained phage resistance and iron tolerance but altered iron (II) and antibiotic sensitivity.
• Stressor-specific genomic adaptations included deletions in phage receptor genes and sweeps in iron-related regulatory/membrane genes.

Conclusions:

• The sequence of environmental stressors significantly shapes phenotypic and genetic resistance outcomes.
• Fitness epistasis and historical contingency are crucial in microbial adaptation.
• Findings inform the design of evolution-informed combination antimicrobial therapies.