{"doi":"10.3390/microorganisms13071532","title":"Genetic Correlates of Synergy Mechanisms of Daptomycin Plus Fosfomycin in Daptomycin-Susceptible and -Resistant Methicillin-Resistant Staphylococcus aureus (MRSA)","abstract":"This study elucidates potential genetic determinants and mechanisms involved in the synergistic effects of daptomycin (DAP) + fosfomycin (FOF) combination therapy. Among 33 clinically derived DAP-susceptible (S)/DAP-resistant (R) isogenic strain pairs, mutations in the mprF gene occurred in 30/33 DAP-R strains, including polymorphisms of L826F (33%) or T345A/L/I (15%). Strain variants of DAP-S CB1483 serially passaged in vitro for 10 days in DAP +/− FOF identified a key non-synonymous mutation in mprF (L826F) only in the DAP monotherapy arm. Interestingly, passage in FOF alone or DAP + FOF prevented the emergence of this mprF mutation following 10-day passage. This L826F mprF polymorphism, associated with a “gain-in-function” phenotype, exhibited increased amounts of lysyl-phosphatidylglycerol (L-PG) in the cell membrane (CM). Transcriptomics revealed a relatively modest number (~10) of distinct genes that were significantly up- or downregulated (≥2 log fold) in both the DAP-S and DAP-R strain pairs upon DAP + FOF exposures (vs. DAP or FOF alone). Of note, DAP + FOF decreased expression of lrgAB and sdrE and increased the expression level of fosB. In a rabbit infective endocarditis (IE) model, the DAP-R CB185 strain treated with DAP +/− FOF showed significantly reduced lrgB expression in vegetations compared with DAP treatment alone. Overall, these findings indicate that DAP + FOF therapy impacts MRSA through multiple specific mechanisms, enhancing bacterial clearance.","journal":"Microorganisms","year":2025,"id":569373,"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":0.9497,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":397628,"name":"Selvi C. Ersoy","orcid":"0000-0002-8792-2061","position":1,"is_corresponding":false},{"id":503839,"name":"Wessam Abdelhady","orcid":null,"position":2,"is_corresponding":false},{"id":1474300,"name":"Ana Domínguez","orcid":"0000-0002-8610-5553","position":3,"is_corresponding":false},{"id":1474611,"name":"Jedidiah Ndam Muyah Manna","orcid":null,"position":4,"is_corresponding":false},{"id":1474612,"name":"Jorge N. Artaza","orcid":null,"position":5,"is_corresponding":false},{"id":1236409,"name":"Reetakshi Mishra","orcid":null,"position":6,"is_corresponding":false},{"id":1145998,"name":"Ahmed M. Elsayed","orcid":"0000-0002-1227-4426","position":7,"is_corresponding":false},{"id":397629,"name":"Richard A. Proctor","orcid":"0000-0003-3011-7958","position":8,"is_corresponding":false},{"id":722085,"name":"Sarah L. Baines","orcid":"0000-0002-0557-0518","position":9,"is_corresponding":false},{"id":236384,"name":"Benjamin P. Howden","orcid":"0000-0003-0237-1473","position":10,"is_corresponding":false},{"id":447480,"name":"Nagendra N. Mishra","orcid":"0000-0002-7475-5794","position":11,"is_corresponding":false},{"id":270150,"name":"Warren E. Rose","orcid":"0000-0001-5012-5993","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:56:59.652443Z","pmid":"40732039","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":[]}