ArticleScience advances2025
Exploring antibiotic resistance in diverse homologs of the dihydrofolate reductase protein family through broad mutational scanning.
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Predicting resistance evolution to guide antibiotic development.Nature reviews. Microbiology · 2026Review
- Evolutionary Convergence on a Dihydrofolate Reductase Mutation Drives Trimethoprim-Sulfamethoxazole Resistance in Burkholderia thailandensis.ACS infectious diseases · 2026Article
- Chaperonin recognition of protein dynamics drives drug resistance.bioRxiv : the preprint server for biology · 2026Article
- A cost-effective and scalable barcoded library construction method for deep mutational scanning studies.PLoS biology · 2026Article
- A combinatorial mutational map of active non-native protein kinases by deep learning guided sequence design.bioRxiv : the preprint server for biology · 2025Article
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Abstract
Antimicrobial resistance studies often focus on individual protein variants, neglecting broader protein family dynamics. Dihydrofolate reductase (DHFR), a key antibiotic target, has been extensively studied using deep mutational scanning, yet resistance mechanisms across this diverse protein family remain poorly understood. Here, we developed a synthetic metagenomics approach using DropSynth, a scalable gene synthesis platform, to construct a phylogenetically diverse library of 1536 DHFR homologs. These sequences, primarily derived from host-associated metagenomes, represent 759 bacterial species, including many clinically relevant pathogens. A multiplexed in vivo assay tested their ability to restore metabolic function and confer trimethoprim resistance in an
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