{"doi":"10.1101/2020.01.20.912303","title":"Exploiting evolutionary trade-offs to combat antibiotic resistance","abstract":"ABSTRACT Antibiotic resistance frequently evolves through fitness trade-offs in which the genetic alterations that confer resistance to a drug can also cause growth defects in resistant cells. Here, through experimental evolution in a microfluidics-based turbidostat, we demonstrate that antibiotic-resistant cells can be efficiently inhibited by amplifying the fitness costs associated with drug-resistance evolution. Using tavaborole-resistant E. coli as a model, we show that genetic mutations in leucyl-tRNA synthetase (that underlie tavaborole resistance) make resistant cells intolerant to norvaline, a chemical analog of leucine that is mistakenly used by tavaborole-resistant cells for protein synthesis. We then show that tavaborole-sensitive cells quickly outcompete tavaborole-resistant cells in the presence of norvaline due to the amplified cost of the molecular defect of tavaborole resistance. This finding illustrates a potentially generalizable approach for combating therapeutic resistance, prolonging the effectiveness of drugs and enabling the use of drugs that are no longer effective due to the rapid evolution of resistance.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":128710,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.948,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":580024,"name":"David L. Stephens","orcid":null,"position":1,"is_corresponding":false},{"id":579411,"name":"Xian Fu","orcid":"0000-0001-9044-8850","position":2,"is_corresponding":false},{"id":6629,"name":"Hui Si Kwok","orcid":"0000-0002-2858-8876","position":3,"is_corresponding":false},{"id":579412,"name":"Jintao Zhang","orcid":"0000-0002-1029-3404","position":4,"is_corresponding":false},{"id":364484,"name":"Yue Shen","orcid":"0000-0002-3276-7295","position":5,"is_corresponding":false},{"id":580025,"name":"Jeffery Sabina","orcid":null,"position":6,"is_corresponding":false},{"id":80034,"name":"Kevin Lee","orcid":"0000-0002-5606-8683","position":7,"is_corresponding":false},{"id":521943,"name":"Harry Lee","orcid":"0000-0002-8991-5201","position":8,"is_corresponding":false},{"id":169060,"name":"Dieter Söll","orcid":"0000-0002-3077-8986","position":9,"is_corresponding":false},{"id":17942,"name":"Sergey Melnikov","orcid":"0000-0002-7525-9039","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-18T23:15:42.522809Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}