{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:19:47Z","timestamp":1782271187533,"version":"3.54.5"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T00:00:00Z","timestamp":1711065600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Antimicrobial resistance (AMR) represents an alarming global challenge to public health. Infections caused by multidrug-resistant <jats:italic>Staphylococcus aureus<\/jats:italic> (<jats:italic>S<\/jats:italic>. <jats:italic>aureus<\/jats:italic>) pose an emerging global threat. Therefore, it is crucial to develop novel compounds with promising antimicrobial activity against <jats:italic>S<\/jats:italic>. <jats:italic>aureus<\/jats:italic> especially those with challenging resistance mechanisms and biofilm formation. Series of bis(thiazol-5-yl)phenylmethane derivatives were evaluated against drug-resistant Gram-positive bacteria. The screening revealed an <jats:italic>S<\/jats:italic>. <jats:italic>aureus<\/jats:italic>-selective mechanism of bis(thiazol-5-yl)phenylmethane derivatives (MIC 2\u201364 <jats:italic>\u03bc<\/jats:italic>g\/mL), while significantly lower activity was observed with vancomycin-resistant <jats:italic>Enterococcus faecalis<\/jats:italic> (MIC 64 <jats:italic>\u03bc<\/jats:italic>g\/mL) (<jats:italic>p&lt;<\/jats:italic>0.05). The most active phenylmethane-based (p-tolyl) derivative, <jats:bold>23a,<\/jats:bold> containing nitro and dimethylamine substituents, and the naphthalene-based derivative, <jats:bold>28b,<\/jats:bold> harboring fluorine and nitro substituents, exhibited strong, near MIC bactericidal activity against <jats:italic>S<\/jats:italic>. <jats:italic>aureus<\/jats:italic> with genetically defined resistance phenotypes such as MSSA, MRSA, and VRSA and their biofilms. The <jats:italic>in silico<\/jats:italic> modeling revealed that most promising compounds <jats:bold>23a<\/jats:bold> and <jats:bold>28b<\/jats:bold> were predicted to bind <jats:italic>S<\/jats:italic>. <jats:italic>aureus<\/jats:italic> MurC ligase. The <jats:bold>23a<\/jats:bold> and <jats:bold>28b<\/jats:bold> formed bonds with MurC residues at binding site, specifically Ser12 and Arg375, indicating consequential interactions essential for complex stability. The <jats:italic>in vitro<\/jats:italic> antimicrobial activity of compound <jats:bold>28b<\/jats:bold> was not affected by the addition of 50% serum. Finally, all tested bis(thiazol-5-yl)phenylmethane derivatives showed favorable cytotoxicity profiles in A549 and THP-1-derived macrophage models. These results demonstrated that bis(thiazol-5-yl)phenylmethane derivatives <jats:bold>23a<\/jats:bold> and <jats:bold>28b<\/jats:bold> could be potentially explored as scaffolds for the development of novel candidates targeting drug-resistant <jats:italic>S<\/jats:italic>. <jats:italic>aureus<\/jats:italic>. Further studies are also warranted to understand <jats:italic>in vivo<\/jats:italic> safety, efficacy, and pharmacological bioavailability of bis(thiazol-5-yl)phenylmethane derivatives.<\/jats:p>","DOI":"10.1371\/journal.pone.0300380","type":"journal-article","created":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T17:25:37Z","timestamp":1711128337000},"page":"e0300380","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Exploring the potential of bis(thiazol-5-yl)phenylmethane derivatives as novel candidates against genetically defined multidrug-resistant Staphylococcus aureus"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0237-9088","authenticated-orcid":true,"given":"Povilas","family":"Kavaliauskas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1182-0253","authenticated-orcid":true,"given":"Waldo","family":"Acevedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan","family":"Naing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birute","family":"Grybaite","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birute","family":"Sapijanskaite-Banevic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramune","family":"Grigaleviciute","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruta","family":"Petraitiene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vytautas","family":"Mickevicius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vidmantas","family":"Petraitis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,3,22]]},"reference":[{"issue":"1","key":"pone.0300380.ref001","doi-asserted-by":"crossref","DOI":"10.1093\/femsre\/fux053","article-title":"Environmental factors influencing the development and spread of antibiotic resistance","volume":"42","author":"J Bengtsson-Palme","year":"2018","journal-title":"FEMS Microbiol Rev"},{"issue":"5","key":"pone.0300380.ref002","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/s41579-021-00649-x","article-title":"Antibiotic resistance in the environment","volume":"20","author":"DGJ Larsson","year":"2022","journal-title":"Nat Rev Microbiol"},{"issue":"1","key":"pone.0300380.ref003","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s12916-020-1507-2","article-title":"Quantifying the economic cost of antibiotic resistance and the impact of related interventions: rapid methodological review, conceptual framework and recommendations for future studies","volume":"18","author":"M Jit","year":"2020","journal-title":"BMC Med"},{"issue":"5","key":"pone.0300380.ref004","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1038\/ja.2017.30","article-title":"The antibiotic resistance crisis, with a focus on the United States","volume":"70","author":"E Martens","year":"2017","journal-title":"J Antibiot (Tokyo)"},{"issue":"4","key":"pone.0300380.ref005","doi-asserted-by":"crossref","first-page":"e00020","DOI":"10.1128\/CMR.00020-18","article-title":"Methicillin-resistant Staphylococcus aureus: Molecular characterization, evolution, and epidemiology","volume":"31","author":"S Lakhundi","year":"2018","journal-title":"Clin Microbiol Rev"},{"issue":"8","key":"pone.0300380.ref006","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1080\/20477724.2020.1824112","article-title":"Methicillin resistant Staphylococcus aureus and public fomites: a review","volume":"114","author":"ZW Jaradat","year":"2020","journal-title":"Pathog Glob Health"},{"issue":"13","key":"pone.0300380.ref007","doi-asserted-by":"crossref","first-page":"7346","DOI":"10.3390\/ijms23137346","article-title":"Thirty years of sRNA-mediated regulation in Staphylococcus aureus: From initial discoveries to in vivo biological implications","volume":"23","author":"G Menard","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"2","key":"pone.0300380.ref008","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.jhin.2017.11.008","article-title":"Staphylococcus aureus and Staphylococcus epidermidis infections on implants","volume":"98","author":"WF Oliveira","year":"2018","journal-title":"J Hosp Infect. 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