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Updated: May 22, 2025
12:32
Quantification of Plasmid-Mediated Antibiotic Resistance in an Experimental Evolution Approach
Published on: December 14, 2019
13.9K
Proteostasis modulates gene dosage evolution in antibiotic-resistant bacteria
Chinmaya Jena1, Saillesh Chinnaraj1, Soham Deolankar1
1Department of Biology, Indian Institute of Science Education and Research, Pune, India.
Elife
|March 12, 2025
Summary
Bacterial antibiotic resistance evolves through gene expression changes. We found that gene duplication, specifically of the folA gene, enhances dihydrofolate reductase (DHFR) levels, contributing to trimethoprim resistance in E. coli.
Area of Science:
- Microbiology
- Evolutionary Biology
- Genetics
Background:
- Antibiotic resistance in bacteria is often driven by changes in gene expression.
- Previous work showed mutations at the mgrB locus in Escherichia coli lead to dihydrofolate reductase (DHFR) overexpression under trimethoprim exposure.
- The folA gene encodes DHFR.
Purpose of the Study:
- To investigate how DHFR levels are further enhanced during bacterial adaptation to trimethoprim.
- To explore the role of gene duplication and copy number evolution in antibiotic resistance.
- To understand the interplay between antibiotic pressure, gene dosage, and proteostasis in bacterial evolution.
Main Methods:
- Studied spontaneous genomic segment duplication encompassing the folA gene in Escherichia coli.
- Compared duplication frequency in wild-type and lon-knockout strains under trimethoprim pressure.
- Performed long-term evolution experiments to observe the dynamics of folA duplications and point mutations.
- Investigated the impact of proteolysis on DHFR mutants and gene copy number evolution.
Main Results:
- Spontaneous duplication of a genomic segment containing folA was observed, significantly increasing DHFR levels.
- Duplication frequency was elevated in a lon-knockout strain, influencing early trimethoprim adaptation.
- Under antibiotic pressure, folA duplications were initially reversed but became stable when coupled with resistance-conferring point mutations.
- Some populations maintained folA duplication even with resistant DHFR mutants to compensate for low abundance.
- Proteolysis of drug-resistant DHFR mutants exacerbated expression demand, favoring gene copy number evolution.
Conclusions:
- Gene dosage evolution, specifically folA duplication, is influenced by expression demand generated by antibiotics.
- Proteostasis, through the proteolysis of drug-resistant DHFR mutants, plays a novel role in determining copy number evolution in antibiotic-resistant bacteria.
- This study proposes a new mechanism linking protein stability and gene copy number changes in bacterial adaptation.
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