{"doi":"10.20944/preprints202301.0110.v1","title":"Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions","abstract":"Plazomicin is a recently U.S. Food and Drug Administration (FDA)-approved semisynthetic aminoglycoside. Its structure consists of a sisomicin scaffold modified by adding a 2(S)-hydroxy aminobutyryl group at the N1 position and a hydroxyethyl substituent at the 6′ position. These substitutions produced a molecule refractory to most aminoglycoside-modifying enzymes. The main enzyme within this group that recognizes plazomicin as substrate is the aminoglycoside 2′-N-acetyltransferase type Ia [AAC(2′)-Ia], which reduces the antibiotic’s potency. Designing formulations that combine an antimicrobial with an inhibitor of resistance is a recognized strategy to extend the useful life of existing antibiotics. We have recently found that several metal ions inhibit acetylation of numerous aminoglycosides catalyzed by the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib]. In particular, Ag1+, which also enhances the effect of aminoglycosides by other mechanisms, is very effective in interfering with AAC(6′)-Ib-mediated resistance to amikacin. Here we report that silver acetate is a potent inhibitor of AAC(2′)-Ia-mediated acetylation of plazomicin in vitro, and it reduces resistance levels of Escherichia coli carrying aac(2′)-Ia. The resistance reversion assays produced equivalent results when the structural gene was expressed under the control of the natural or the blaTEM-1 promoters. The antibiotic effect of plazomicin in combination with silver was bactericidal, and the mix did not show significant toxicity to human embryonic kidney 293 (HEK293) cells.","journal":"Preprints.org","year":2023,"id":394008,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9514,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1071521,"name":"Angel J. Magaña","orcid":"0009-0007-7541-1938","position":1,"is_corresponding":false},{"id":1168493,"name":"Tung Thanh Tran","orcid":"0000-0002-9829-2990","position":2,"is_corresponding":false},{"id":1072197,"name":"Jan Sklenicka","orcid":null,"position":3,"is_corresponding":false},{"id":507199,"name":"Kimberly Phan","orcid":"0009-0006-5727-1815","position":4,"is_corresponding":false},{"id":1125836,"name":"Brian Eykholt","orcid":null,"position":5,"is_corresponding":false},{"id":434508,"name":"Verónica Jiménez","orcid":"0000-0002-0744-8137","position":6,"is_corresponding":false},{"id":239691,"name":"María Soledad Ramirez","orcid":"0000-0002-9904-7890","position":7,"is_corresponding":false},{"id":239692,"name":"Marcelo E. Tolmasky","orcid":"0000-0002-6298-7811","position":8,"is_corresponding":false},{"id":1125835,"name":"David Chek Ling Ngo","orcid":null,"position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:10.334330Z","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":[]}