{"doi":"10.1101/2020.08.31.275693","title":"Disrupting the ArcA regulatory network increases tetracycline susceptibility of Tet <sup>R</sup> <i>Escherichia coli</i>","abstract":"ABSTRACT There is an urgent need for strategies to discover secondary drugs to prevent or disrupt antimicrobial resistance (AMR), which is causing &gt;700,000 deaths annually. Here, we demonstrate that tetracycline resistant (Tet R ) Escherichia coli undergoes global transcriptional and metabolic remodeling, including down-regulation of tricarboxylic acid cycle and disruption of redox homeostasis, to support consumption of the proton motive force for tetracycline efflux. Targeted knockout of ArcA, identified by network analysis as a master regulator among 25 transcription factors of this new compensatory physiological state, significantly increased the susceptibility of Tet R E. coli to tetracycline treatment. A drug, sertraline, which generated a similar metabolome profile as the arcA knockout strain also synergistically re-sensitized Tet R E. coli to tetracycline. The potentiating effect of sertraline was eliminated upon knocking out arcA , demonstrating that the mechanism of synergy was through action of sertraline on the tetracycline-induced ArcA network in the Tet R strain. Our findings demonstrate that targeting mechanistic drivers of compensatory physiological states could be a generalizable strategy to re-sensitize AMR pathogens to lost antibiotics.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":125327,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9566,"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":441560,"name":"Min Pan","orcid":"0000-0002-9781-0637","position":1,"is_corresponding":false},{"id":571237,"name":"Amardeep Kaur","orcid":"0000-0002-2762-736X","position":2,"is_corresponding":false},{"id":307005,"name":"Vivek Srinivas","orcid":"0000-0002-0265-1873","position":3,"is_corresponding":false},{"id":571238,"name":"Ananya Dash","orcid":"0000-0001-5679-1065","position":4,"is_corresponding":false},{"id":558635,"name":"Rupa Immanuel","orcid":"0000-0002-3642-9605","position":5,"is_corresponding":false},{"id":400246,"name":"Nitin S. Baliga","orcid":"0000-0001-9157-5974","position":6,"is_corresponding":false},{"id":400244,"name":"Mario L. Arrieta‐Ortiz","orcid":"0000-0002-7111-8087","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-18T23:15:15.482227Z","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":[]}