{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T07:47:09Z","timestamp":1769068029283,"version":"3.49.0"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,8,27]],"date-time":"2022-08-27T00:00:00Z","timestamp":1661558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"MIUR","doi-asserted-by":"publisher","award":["PRIN2017SFBFER"],"award-info":[{"award-number":["PRIN2017SFBFER"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background: Methicillin-resistant Staphylococcus aureus (MRSA) with intermediate resistance to Vancomycin (VISA) is reported worldwide. These strains frequently emerge among hospital-associated (HA)-MRSA and rarely within community-acquired (CA)-MRSA. Here, the genomic and transcriptomic adaptations distinguishing VISA daptomycin resistant (DAP-R) CA-MRSA, which emerged in a hospitalized patient under glycopeptide treatment, were explored. Methods: Whole-genome sequencing, RNA-Seq and bioinformatics were carried out. Results: Our CA-MRSA clustered in the USA400 lineage showing additional antimicrobial resistance (AMR) versus DAP and glycopeptides. Resistomics revealed adaptations related to glycopeptide, daptomycin and rifampin resistance (mprF nsSNPS and overexpression of glycopeptide and daptomycin-resistance related genes). Similar changes were detected in virulence traits (agrA HI-nsSNPs and toxin gene underexpression), in which a decrease was observed despite the abundance of virulence-related genes. Our results predicted a balance in adaptations, decreasing the virulence and biological costs to support the co-occurrence of extensive AMR in a hypervirulent genomic background. Conclusion: Our data show that VISA DAP-R CA-MRSA shifts the potential hypervirulent behavior of CA-MRSA towards the acquisition and maintenance of extensive AMR, by a decrease in virulence and biological costs mediated by a \u201ccompensatory modulatory mutation\u201d silencing the Agr quorum-sensing cascade.<\/jats:p>","DOI":"10.3390\/antibiotics11091159","type":"journal-article","created":{"date-parts":[[2022,8,28]],"date-time":"2022-08-28T21:22:56Z","timestamp":1661721776000},"page":"1159","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Balancing the Virulence and Antimicrobial Resistance in VISA DAP-R CA-MRSA Superbug"],"prefix":"10.3390","volume":"11","author":[{"given":"Rossella","family":"Salemi","sequence":"first","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Zega","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elvira","family":"Aguglia","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flavia","family":"Lo Verde","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Pigola","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\/0000-0003-1594-7427","authenticated-orcid":false,"given":"Stefania","family":"Stefani","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":[[2022,8,27]]},"reference":[{"key":"ref_1","unstructured":"WHO (2020, January 01). WHO Publishes List of Bacteria for which New Antibiotics Are Urgently Needed. Available online: https:\/\/www.who.int\/news\/item\/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1097\/01.blo.0000175714.68624.74","article-title":"Biofilms and Antimicrobial Resistance","volume":"437","author":"Patel","year":"2005","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1128\/AAC.47.7.2283-2292.2003","article-title":"Quantitative analysis of gentamicin, azithromycin, telithromycin, ciprofloxacin, moxifloxacin, and oritavancin (LY333328) activities against intracellular Staphylococcus aureus in mouse J774 macrophages","volume":"47","author":"Seral","year":"2003","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3467","DOI":"10.1128\/JB.182.12.3467-3474.2000","article-title":"Differential expression of over 60 chromosomal genes in Escherichia coli by constitutive expression of MarA","volume":"182","author":"Barbosa","year":"2000","journal-title":"J. Bacteriol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1128\/AAC.01275-10","article-title":"Klebsiella pneumoniae outer membrane porins OmpK35 and OmpK36 play roles in both antimicrobial resistance and virulence","volume":"55","author":"Tsai","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3694","DOI":"10.1128\/AAC.00172-08","article-title":"Benefit of having multiple ampD genes for acquiring beta-lactam resistance without losing fitness and virulence in Pseudomonas aeruginosa","volume":"52","author":"Moya","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1128\/JB.00911-10","article-title":"The sensor kinase CbrA is a global regulator that modulates metabolism, virulence, and antibiotic resistance in Pseudomonas aeruginosa","volume":"193","author":"Yeung","year":"2011","journal-title":"J. Bacteriol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1128\/CMR.00081-09","article-title":"Community-associated methicillin-resistant Staphylococcus aureus: Epidemiology and clinical consequences of an emerging epidemic","volume":"23","author":"David","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"521","DOI":"10.3390\/antibiotics4040521","article-title":"Livestock-Associated MRSA: The Impact on Humans","volume":"4","author":"Cuny","year":"2015","journal-title":"Antibiotics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.2147\/IDR.S209591","article-title":"Association between cell growth and vancomycin resistance in clinical community-associated methicillin-resistant Staphylococcus aureus","volume":"12","author":"Yamaguchi","year":"2019","journal-title":"Infect. Drug Resist."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Almeida, S.T., Paulo, A.C., Babo, J., Borralho, J., Figueiredo, C., Gon\u00e7alves, B., Lan\u00e7a, J., Louro, M., Morais, H., and Queiroz, J. (2021). Absence of methicillin-resistant Staphylococcus aureus colonization among immunocompetent healthy adults: Insights from a longitudinal study. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0253739"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.resmic.2004.01.012","article-title":"Shaping bacterial genomes with integrative and conjugative elements","volume":"155","author":"Burrus","year":"2004","journal-title":"Res. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Handel, A., Regoes, R.R., and Antia, R. (2006). The role of compensatory mutations in the emergence of drug resistance. PLoS Comput. Biol., 2.","DOI":"10.1371\/journal.pcbi.0020137"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41579-018-0147-4","article-title":"Methicillin-resistant Staphylococcus aureus: An overview of basic and clinical research","volume":"17","author":"Turner","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_15","first-page":"269","article-title":"Vancomycin Resistance in Staphylococcus aureus","volume":"90","author":"McGuinness","year":"2017","journal-title":"Yale J. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"415","DOI":"10.4103\/ijmm.IJMM_17_311","article-title":"Survivability and fitness cost of heterogeneous vancomycin-intermediate Staphylococcus aureus","volume":"35","author":"Singh","year":"2017","journal-title":"Indian J. Med. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s10096-016-2581-4","article-title":"In Vivo development of daptomycin resistance in vancomycin-susceptible methicillin-resistant Staphylococcus aureus severe infections previously treated with glycopeptides","volume":"35","author":"Capone","year":"2016","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_18","first-page":"391","article-title":"The Genesis and Emergence of Community-Associated Methicillin-Resistant Staphylococcus aureus (CA-MRSA): An Example of Evolution in Action?","volume":"8","author":"Gillen","year":"2015","journal-title":"Answ. Res. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.tim.2004.06.004","article-title":"Staphylococcus aureus: Superbug, super genome?","volume":"12","author":"Lindsay","year":"2004","journal-title":"Trends Microbiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1007\/s00018-010-0389-4","article-title":"Mobile genetic elements of Staphylococcus aureus","volume":"67","author":"Malachowa","year":"2010","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Jamrozy, D., Coll, F., Mather, A.E., Harris, S.R., Harrison, E.M., MacGowan, A., Karas, A., Elston, T., T\u00f6r\u00f6k, M.E., and Parkhill, J. (2017). Evolution of mobile genetic element composition in an epidemic methicillin-resistant Staphylococcus aureus: Temporal changes correlated with frequent loss and gain events. BMC Genom., 18.","DOI":"10.1186\/s12864-017-4065-z"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1128\/AAC.48.6.1953-1959.2004","article-title":"tcaA inactivation increases glycopeptide resistance in Staphylococcus aureus","volume":"48","author":"Maki","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1007\/s12275-013-3088-7","article-title":"Prevalence of amino acid changes in the yvqF, vraSR, graSR, and tcaRAB genes from vancomycin intermediate resistant Staphylococcus aureus","volume":"51","author":"Yoo","year":"2013","journal-title":"J. Microbiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ijantimicag.2013.10.001","article-title":"dltA overexpression: A strain-independent keystone of daptomycin resistance in methicillin-resistant Staphylococcus aureus","volume":"43","author":"Cafiso","year":"2014","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Cafiso, V., Bertuccio, T., Spina, D., Purrello, S., Campanile, F., Di Pietro, C., Purrello, M., and Stefani, S. (2012). Modulating activity of vancomycin and daptomycin on the expression of autolysis cell-wall turnover and membrane charge genes in hVISA and VISA strains. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0029573"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Mishra, N.N., Bayer, A.S., Weidenmaier, C., Grau, T., Wanner, S., Stefani, S., Cafiso, V., Bertuccio, T., Yeaman, M.R., and Nast, C.C. (2014). Phenotypic and genotypic characterization of daptomycin-resistant methicillin-resistant Staphylococcus aureus strains: Relative roles of mprF and dlt operons. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107426"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.3389\/fmicb.2020.01893","article-title":"Genomic and Long-Term Transcriptomic Imprints Related to the Daptomycin Mechanism of Action Occurring in Daptomycin-and Methicillin-Resistant Staphylococcus aureus Under Daptomycin Exposure","volume":"11","author":"Cafiso","year":"2020","journal-title":"Front. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1086\/657419","article-title":"Comparative analysis of virulence and toxin expression of global community-associated methicillin-resistant Staphylococcus aureus strains","volume":"202","author":"Li","year":"2010","journal-title":"J. Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1099\/mic.0.2007\/011874-0","article-title":"agr function in clinical Staphylococcus aureus isolates","volume":"154","author":"Traber","year":"2008","journal-title":"Microbiology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1128\/CMR.00059-12","article-title":"Antimicrobial resistance and virulence: A successful or deleterious association in the bacterial world?","volume":"26","author":"Beceiro","year":"2013","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_31","unstructured":"(2022, July 01). EUCAST. Available online: https:\/\/www.eucast.org\/eucast_news\/news_singleview\/?tx_ttnews%5Btt_news%5D=459cHash=160a5b91371e598957e10178fb3aa143."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1136\/jcp.2004.024091","article-title":"Survivability of vancomycin resistant enterococci and fitness cost of vancomycin resistance acquisition","volume":"58","author":"Ramadhan","year":"2005","journal-title":"J. Clin. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1111\/j.1574-695X.2007.00298.x","article-title":"agr-Genotyping and transcriptional analysis of biofilm-producing Staphylococcus aureus","volume":"51","author":"Cafiso","year":"2007","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Cafiso, V., Lo Verde, F., Zega, A., Pigola, G., Rostagno, R., Borr\u00e8, S., and Stefani, S. (2021). Genomic Characterization of a New Biofilm-Forming and Adhesive ST398 Human-Adapted MSSA Lineage Causing Septic Knee Arthritis Following Surgical Reconstruction. Microorganisms, 9.","DOI":"10.3390\/microorganisms9020305"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2640","DOI":"10.1093\/jac\/dks261","article-title":"Identification of acquired antimicrobial resistance genes","volume":"67","author":"Zankari","year":"2012","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4305","DOI":"10.1128\/JCM.01979-14","article-title":"Comparing whole-genome sequencing with Sanger sequencing for spa typing of methicillin-resistant Staphylococcus aureus","volume":"52","author":"Bartels","year":"2014","journal-title":"J. Clin. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1128\/JCM.03617-13","article-title":"Real-time whole-genome sequencing for routine typing, surveillance, and outbreak detection of verotoxigenic Escherichia coli","volume":"52","author":"Joensen","year":"2014","journal-title":"J. Clin. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Carattoli, A., and Hasman, H. (2020). PlasmidFinder and in silico pMLST: Identification and typing of plasmid replicons in whole-genome sequencing (WGS). Horizontal Gene Transfer, Humana.","DOI":"10.1007\/978-1-4939-9877-7_20"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1093\/jac\/dkaa390","article-title":"Detection of mobile genetic elements associated with antibiotic resistance in Salmonella enterica using a newly developed web tool: MobileElementFinder","volume":"76","author":"Johansson","year":"2021","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"W347","DOI":"10.1093\/nar\/gkr485","article-title":"PHAST: A fast phage search tool","volume":"39","author":"Zhou","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.meegid.2013.06.009","article-title":"Analysis of prophages harboured by the human-adapted subpopulation of Staphylococcus aureus CC398","volume":"18","author":"Corvaglia","year":"2013","journal-title":"Infect. Genet. Evol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Huang","year":"2009","journal-title":"Nat. Protoc."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/11\/9\/1159\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:16:34Z","timestamp":1760141794000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/11\/9\/1159"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,27]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["antibiotics11091159"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics11091159","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,27]]}}}