{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:14:33Z","timestamp":1760058873709,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EU funding with the MUR PNRR \u201cEXTENDED PARTNERSHIP INITIATIVE ON EMERGENCE INFECTIOUS DISEASE\u201d","award":["PE00000007 INF-ACT"],"award-info":[{"award-number":["PE00000007 INF-ACT"]}]},{"name":"\u201cLinea intervento 1 Progetti di Ricerca Collaborativa PIACERI 2024\u20132026\u201d from the University of Catania, Italy","award":["PE00000007 INF-ACT"],"award-info":[{"award-number":["PE00000007 INF-ACT"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background: In Staphylococcus aureus, antimicrobial resistance (AMR) imposes significant fitness costs (FCs), including reduced growth rate, interbacterial competitiveness, and virulence. However, the FC molecular basis remains poorly understood. This study investigated the FC omic basis and compensatory adaptations in high-risk HA-, LA-, and CA-MRSA, acquiring mono- or cross-resistance to second-line daptomycin (DAP) and dalbavancin (DAL), as well as reduced susceptibility (RS) to first-line glycopeptides, i.e., vancomycin and teicoplanin (GLYs, i.e., VAN, TEC), related to the specific mechanism of action (MOA)-related AMR-mechanisms and genomic backgrounds, paying increasing FCs. Methods: The FC omic basis associated with mono- or cross- DAP-\/DAL-R and GLY-RS were investigated by integrated omics. This study focused on core-genome essential (EG) and accessory virulence gene (VG) SNPomics and transcriptomics by Illumina MiSeq whole-genome sequencing, RNA-seq, and bioinformatic analysis. Results: Moderate impact nsSNPs were identified in EGs related to vital cellular functions and VGs. Comparative EG transcriptomics revealed differential expressions and key dysregulations\u2014via asRNAs\u2014prevalently affecting the protein synthesis and cell-envelope EG clusters, as well as the VG cluster. Conclusions: Our data, firstly, underlined the EG and VG mutation- and transcription-driven omic-based FC burden and the compensatory adaptations associated with the emergence of mono-DAP-R, cross-DAP-R\/hGISA, and DAP-R\/DAL-R\/GISA, linked to specific MOA-related AMR-mechanisms and genomic backgrounds in high-risk HA-, LA-, and CA-MRSA.<\/jats:p>","DOI":"10.3390\/antibiotics14050465","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T07:44:58Z","timestamp":1746171898000},"page":"465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mutation- and Transcription-Driven Omic Burden of Daptomycin\/Dalbavancin-R and Glycopeptide-RS Fitness Costs in High-Risk MRSA: A Nexus in Antimicrobial Resistance Mechanisms\u2014Genome Proneness\u2014Compensatory Adaptations"],"prefix":"10.3390","volume":"14","author":[{"given":"Eleonora","family":"Chines","sequence":"first","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"},{"name":"Department of Public Health, Experimental, and Forensic Medicine, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4534-4176","authenticated-orcid":false,"given":"Gaia","family":"Vertillo Aluisio","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Lina","family":"Mezzatesta","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1491-4973","authenticated-orcid":false,"given":"Maria","family":"Santagati","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0785-7934","authenticated-orcid":false,"given":"Viviana","family":"Cafiso","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1089\/mdr.2020.0426","article-title":"Fitness Cost of Antibiotic Resistance in Staphylococcus aureus: A Systematic Review","volume":"27","author":"Touati","year":"2021","journal-title":"Microb. 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