{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T01:49:53Z","timestamp":1779155393792,"version":"3.51.4"},"reference-count":33,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T00:00:00Z","timestamp":1693353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Methicillin-resistant Staphylococcus aureus (MRSA) emerged as one of the leading causes of persistent human infections and makes it difficult to treat bacteremia, especially with biofilm formation. In this work, we investigated the in vitro synergism between Linezolid (LNZ) and Vancomycin (VAN) with a 2-mercaptobenzothiazole derivative, resulting in a new small-molecule antibacterial compound that we named BTZ2e, on several clinical MRSA, MRSE (methicillin-resistant Staphylococcus epidermidis) and control (ATCC Collection) strains in their planktonic and biofilms cultures. The broth microdilution method evaluated the susceptibility of planktonic cells to each investigated antibiotic combined with BTZ2e. The biofilm\u2019s metabolic activity was studied with the XTT reduction assay. As a result, in this study, biofilm formation was significantly suppressed by the BTZ2e treatment. In terms of minimal biofilm inhibitory concentration (MBIC), BTZ2e revealed an MBIC50 value of 32 \u03bcg\/mL against methicillin-susceptible S. aureus (MSSA) and 16 \u03bcg\/mL against methicillin-resistant S. aureus ATCC 43300 biofilms. An inhibition range of 32 \u03bcg\/mL and 256 \u03bcg\/mL was registered for the clinical isolates. Interestingly, a synergistic effect (FICI \u2264 0.5) was encountered for the combination of BTZ2e with LNZ and VAN on several planktonic and sessile strains. In particular, the best result against planktonic cells emerged as a result of the synergistic association between LNZ and BTZ2e, while against sessile cells, the best synergistic association resulted from VAN and BTZ2e. The consistent results indicate BTZ2e as a promising adjuvant against multi-resistant strains such as MRSA and MRSE.<\/jats:p>","DOI":"10.3390\/molecules28176348","type":"journal-article","created":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T10:30:52Z","timestamp":1693391452000},"page":"6348","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Antimicrobial Synergistic Effects of Linezolid and Vancomycin with a Small Synthesized 2-Mercaptobenzothiazole Derivative: A Challenge for MRSA Solving"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9185-8405","authenticated-orcid":false,"given":"Marilena","family":"Muraglia","sequence":"first","affiliation":[{"name":"Dipartimento di Farmacia-Scienze del Farmaco, Universit\u00e0 Degli Studi di Bari \u201cA. Moro\u201d, Campus Universitario E. Quagliarello Via Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigida Immacolata Pia","family":"Schiavone","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia-Scienze del Farmaco, Universit\u00e0 Degli Studi di Bari \u201cA. Moro\u201d, Campus Universitario E. Quagliarello Via Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5462-4650","authenticated-orcid":false,"given":"Antonio","family":"Rosato","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia-Scienze del Farmaco, Universit\u00e0 Degli Studi di Bari \u201cA. Moro\u201d, Campus Universitario E. Quagliarello Via Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1717-2197","authenticated-orcid":false,"given":"Maria Lisa","family":"Clodoveo","sequence":"additional","affiliation":[{"name":"Dipartimento Interdisciplinare di Medicina, Universit\u00e0 degli Studi di Bari \u201cA. Moro\u201d, Piazza Giulio Cesare 11, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6951-1103","authenticated-orcid":false,"given":"Filomena","family":"Corbo","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia-Scienze del Farmaco, Universit\u00e0 Degli Studi di Bari \u201cA. Moro\u201d, Campus Universitario E. Quagliarello Via Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,30]]},"reference":[{"key":"ref_1","unstructured":"(2023, July 02). Available online: https:\/\/www.who.int\/news\/item\/09-12-2022-report-signals-increasing-resistance-to-antibiotics-in-bacterial-infections-in-humans-and-need-for-better-data."},{"key":"ref_2","unstructured":"(2023, July 02). (EARS-Net) 2017. Available online: https:\/\/www.ecdc.europa.eu\/en\/antimicrobial-resistance\/surveillance-and-disease-data\/report."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1128\/CMR.00042-09","article-title":"Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: Resistance mechanisms, labora-tory detection, and clinical implications","volume":"23","author":"Howden","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_4","unstructured":"O\u2019Neill, J. (2016). Tackling Drug-Resistant Infections Globally: Final Report and Recommendations the Review on Antimicrobial Resistance, Wellcome Trust and UK Government."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/cmdc.202000677","article-title":"Therapeutic strategies to counteract antibiotic resistance in MRSA biofilm-associated infections","volume":"16","author":"Cascioferro","year":"2021","journal-title":"ChemMedChem"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"309","DOI":"10.7326\/0003-4819-144-5-200603070-00005","article-title":"Emergence of community-acquired methicillin-resistant Staphylococcus aureus USA 300 clone as the predominant cause of skin and soft-tissue infections","volume":"144","author":"King","year":"2006","journal-title":"Ann. Intern. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1093\/cid\/cir034","article-title":"Clinical practice guidelines by the infectious diseases society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: Executive summary","volume":"52","author":"Liu","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Nandhini, P., Kumar, P., Mickymaray, S., Alothaim, A.S., Somasundaram, J., and Rajan, M. (2022). Recent Developments in Methicillin-Resistant Staphylococcus aureus (MRSA) Treatment: A. Review. Antibiotics, 11.","DOI":"10.3390\/antibiotics11050606"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Altowayan, W.M., Mobark, M.A., Alharbi, A., Alduhami, A.A., and Rabbani, S.I. The influence of vancomycin on renal functions, the predictors and associated factors for nephrotoxicity. PLoS ONE, 2023 18.","DOI":"10.1371\/journal.pone.0284223"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"908","DOI":"10.3389\/fmicb.2020.00908","article-title":"Dynamic Changes of Staphylococcus aureus Susceptibility to Vancomycin, Teicoplanin, and Linezolid in a Central Teaching Hospital in Shanghai, China, 2008-2018","volume":"11","author":"Jian","year":"2020","journal-title":"Front Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1093\/jac\/47.2.171","article-title":"In situ measurement of linezolid and vancomycin concentrations in intravascular catheter-associated biofilm","volume":"47","author":"Wilcox","year":"2001","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1476-0711-4-2","article-title":"In vitro activity of vancomycin, quinupristin\/dalfopristin, and linezolid against intact and disrupted biofilms of staphylococci","volume":"4","author":"Rao","year":"2005","journal-title":"Ann. Clin. Microbiol. Antimicrob."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"111","DOI":"10.4046\/trd.2021.0122","article-title":"Concise Clinical Review of Hematologic Toxicity of Linezolid in Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: Role of Mitochondria","volume":"85","author":"Oehadian","year":"2022","journal-title":"Tuberc. Respir Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"697","DOI":"10.3390\/antibiotics12040697","article-title":"Effectiveness and Safety of Linezolid Versus Vancomycin, Teicoplanin, or Daptomycin against Methicillin-Resistant Staphylococcus aureus Bacteremia: A Systematic Review and Meta-Analysis","volume":"12","author":"Kawasuji","year":"2023","journal-title":"Antibiotics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"496","DOI":"10.3390\/antibiotics9080496","article-title":"Synergy of Linezolid with Several Antimicrobial Agents against Linezolid-Methicillin-Resistant Staphylococcal Strains","volume":"9","author":"Valderrama","year":"2020","journal-title":"Antibiotics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1093\/cid\/ciq146","article-title":"Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children","volume":"52","author":"Liu","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.2147\/IDR.S175978","article-title":"In vitro activity and post-antibiotic effects of linezolid in combination with fosfomycin against clinical isolates of Staphylococcus aureus","volume":"11","author":"Chen","year":"2018","journal-title":"Infect. Drug Resist."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lee, Y.C., Chen, P.Y., Wang, J.T., and Chan, S.D. (2019). A study on combination of daptomycin with selected antimicrobial agents: In vitro synergistic effect of MIC value of 1mg\/L against MRSA strains. BMC Pharmacol. Toxicol., 20.","DOI":"10.1186\/s40360-019-0305-y"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"181758","DOI":"10.1155\/2013\/181758","article-title":"Synthesis and Antimicrobial Evaluation of a New Series of N-1, 3-Benzothiazol-2-ylbenzamides","volume":"2013","author":"Armenise","year":"2013","journal-title":"J. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1002\/jhet.2222","article-title":"1, 3-Benzothiazoles as Antimicrobial Agents","volume":"52","author":"Defrenza","year":"2015","journal-title":"J. Heterocycl. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1002\/ardp.200900092","article-title":"Synthesis and Biological Evaluation of 2-Mercapto-1,3-benzothiazole Derivatives with Potential Antimicrobial Activity","volume":"342","author":"Franchini","year":"2009","journal-title":"Arch. Pharm."},{"key":"ref_22","unstructured":"NCCLS (2003). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, Approved Standard M7-A6, National Committee for Clinical Laboratory Standards. [6th ed.]."},{"key":"ref_23","unstructured":"(2021). Performance Standards for Antimicrobial Susceptibility Testing, 31st ed (Standard No. CLSI 2021. MS-100)."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1111\/j.1600-0463.2007.apm_630.x","article-title":"Quantification of biofilm in microtiter plates: Overview of testing conditions and practical recommendations for assessment of biofilm production by staphylococci","volume":"115","author":"Hola","year":"2007","journal-title":"APMIS"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1021\/np400394c","article-title":"Biological evaluation of hyperforin and its hydrogenated analogue on bacterial growth and biofilm production","volume":"76","author":"Schiavone","year":"2013","journal-title":"J. Nat. Prod."},{"key":"ref_26","unstructured":"(2007). Performance Standards for Antimicrobial Susceptibility Testing (Standard No. CLSI 2021. M100-S17)."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1128\/JCM.41.1.506-508.2003","article-title":"Uses and limitation of the XTT assay in studies of Candida growth and metabolism","volume":"41","author":"Kuhn","year":"2003","journal-title":"J. Clin. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"637","DOI":"10.3390\/antibiotics9100637","article-title":"Anti-Biofilm Inhibitory Synergistic Effects of Combinations of Essential Oils and Antibiotics","volume":"9","author":"Rosato","year":"2020","journal-title":"Antibiotics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.foodchem.2008.07.062","article-title":"Antioxidant and antimicrobial activities of consecutive extracts from Galla chinesis: The polarity affects the bioactivities","volume":"113","author":"Tian","year":"2009","journal-title":"Food Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1159\/000318265","article-title":"Efficacy of Chlorhexidine, Polihexanide and Tissue-Tolerable Plasma against Pseudomonas aeruginosa Biofilms Grown on Polystyrene and Silicone Materials","volume":"23","author":"Matthes","year":"2010","journal-title":"Skin Pharmacol. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s00114-002-0305-3","article-title":"A review on usnic acid, an interesting natural compound","volume":"89","author":"Cocchietto","year":"2002","journal-title":"Naturwissenschaften"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2773","DOI":"10.1007\/s10856-011-4445-x","article-title":"Mechanical effects, antimicrobial efficacy and cytotoxicity of usnic acid as a biofilm prophylaxis in PMMA","volume":"22","author":"Kim","year":"2011","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1128\/AAC.48.5.1879-1881.2004","article-title":"Rapid colorimetric assay for antimicrobial susceptibility testing of Pseudomonas aeruginosa","volume":"48","author":"Tunney","year":"2004","journal-title":"Antimicrob. Agent Chemother."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/17\/6348\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:43:10Z","timestamp":1760128990000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/17\/6348"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,30]]},"references-count":33,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["molecules28176348"],"URL":"https:\/\/doi.org\/10.3390\/molecules28176348","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,30]]}}}