{"doi":"10.1128/aac.01627-23","title":"Sensitizing methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) to cefuroxime: the synergic effect of bicarbonate and the wall teichoic acid inhibitor ticlopidine","abstract":"ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) strains are a major challenge for clinicians due, in part, to their resistance to most β-lactams, the first-line treatment for methicillin-susceptible S. aureus . A phenotype termed “NaHCO 3 -responsiveness” has been identified, wherein many clinical MRSA isolates are rendered susceptible to standard-of-care β-lactams in the presence of physiologically relevant concentrations of NaHCO 3 , in vitro and ex vivo ; moreover, such “NaHCO 3 -responsive” isolates can be effectively cleared by β-lactams from target tissues in experimental infective endocarditis (IE). One mechanistic impact of NaHCO 3 exposure on NaHCO 3 -responsive MRSA is to repress WTA synthesis. This NaHCO 3 effect mimics the phenotype of tarO -deficient MRSA, including sensitization to the PBP2-targeting β-lactam, cefuroxime (CFX). Herein, we further investigated the impacts of NaHCO 3 exposure on CFX susceptibility in the presence and absence of a WTA synthesis inhibitor, ticlopidine (TCP), in a collection of clinical MRSA isolates from skin and soft tissue infections (SSTI) and bloodstream infections (BSI). NaHCO 3 and/or TCP enhanced susceptibility to CFX in vitro , by both minimum inhibitor concentration (MIC) and time-kill assays, as well as in an ex vivo simulated endocarditis vegetations (SEV) model, in NaHCO 3 -responsive MRSA. Furthermore, in experimental IE (presumably in the presence of endogenous NaHCO 3 ), pre-exposure to TCP prior to infection sensitized the NaHCO 3 -responsive MRSA strain (but not the non-responsive strain) to enhanced clearances by CFX in target tissues. These data support the notion that NaHCO 3 is acting similarly to WTA synthesis inhibitors, and that such inhibitors have potential translational applications in the treatment of certain MRSA strains in conjunction with specific β-lactam agents.","journal":"Antimicrobial Agents and Chemotherapy","year":2024,"id":457190,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":397629,"name":"Richard A. Proctor","orcid":"0000-0003-3011-7958","position":1,"is_corresponding":false},{"id":270150,"name":"Warren E. Rose","orcid":"0000-0001-5012-5993","position":2,"is_corresponding":false},{"id":503839,"name":"Wessam Abdelhady","orcid":null,"position":3,"is_corresponding":false},{"id":1130708,"name":"Sook‐Ha Fan","orcid":"0000-0003-0556-238X","position":4,"is_corresponding":false},{"id":1282872,"name":"Sabrina L. Madrigal","orcid":null,"position":5,"is_corresponding":false},{"id":1145998,"name":"Ahmed M. Elsayed","orcid":"0000-0002-1227-4426","position":6,"is_corresponding":false},{"id":232760,"name":"Henry F. Chambers","orcid":"0000-0001-5317-4491","position":7,"is_corresponding":false},{"id":940400,"name":"Rita G. Sobral","orcid":"0000-0003-4533-7531","position":8,"is_corresponding":false},{"id":397631,"name":"Arnold S. Bayer","orcid":"0000-0003-1968-0192","position":9,"is_corresponding":false},{"id":397628,"name":"Selvi C. Ersoy","orcid":"0000-0002-8792-2061","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:03:37.136946Z","pmid":"38349162","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":[]}