{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:37:46Z","timestamp":1772253466555,"version":"3.50.1"},"reference-count":34,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"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>The increasing prevalence of antimicrobial resistance among ESKAPE group pathogens presents a significant challenge in the healthcare sector, contributing to higher morbidity and mortality rates globally. Thus, it is essential to develop novel antimicrobial agents effective against drug-resistant pathogens. In this study, we report the synthesis and <jats:italic>in vitro<\/jats:italic> antimicrobial activity characterization of novel <jats:italic>N<\/jats:italic>-substituted <jats:italic>\u03b2<\/jats:italic>-amino acid derivatives bearing 2-hydroxyphenyl core against multidrug-resistant bacterial pathogens. The synthesized compounds (<jats:bold>2\u201326<\/jats:bold>) exhibited promising antimicrobial activity specifically against Gram-positive bacteria, with minimum inhibitory concentrations (MIC) ranging from 4 to 128 \u00b5g\/mL. Compounds <jats:bold>9<\/jats:bold> (R\u2009=\u20094-nitrophenyl), <jats:bold>17<\/jats:bold> (R\u2009=\u20095-nitro-2-thienyl), <jats:bold>18<\/jats:bold> (R\u2009=\u20095-nitro-2-furyl), thiosemicarbazide <jats:bold>16<\/jats:bold>, and <jats:bold>26<\/jats:bold> exhibited the most promising activity against <jats:italic>Staphylococcus aureus<\/jats:italic> MRSA USA300 lineage strain TCH-1516, with MIC values between 4 and 16 \u00b5g\/mL. Compound <jats:bold>26<\/jats:bold> demonstrated strong antimicrobial activity against both <jats:italic>S. aureus<\/jats:italic> TCH-1516 and <jats:italic>E. faecalis<\/jats:italic> AR-0781, with the activity comparable to control antibiotics. Furthermore, compound <jats:bold>26<\/jats:bold> exhibited antifungal activity drug-resistant against <jats:italic>Candida albicans<\/jats:italic> AR-0761 (MIC 16 \u00b5g\/mL). These findings indicate that <jats:italic>N<\/jats:italic>-substituted <jats:italic>\u03b2<\/jats:italic>-amino acid derivatives with a 2-hydroxyphenyl core warrant further investigation as a potential scaffold for the further development of antimicrobial agents based on compound <jats:bold>26<\/jats:bold> targeting Gram-positive pathogens and drug-resistant <jats:italic>C. albicans<\/jats:italic> AR-0761.<\/jats:p>","DOI":"10.1371\/journal.pone.0311715","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T17:33:22Z","timestamp":1749749602000},"page":"e0311715","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Synthesis of novel N-substituted \u03b2-amino acid derivatives bearing 2-hydroxyphenyl moieties as promising antimicrobial candidates targeting multidrug-resistant Gram-positive pathogens"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0237-9088","authenticated-orcid":true,"given":"Povilas","family":"Kavaliauskas","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birut\u0117","family":"Grybait\u0117","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birute","family":"Sapijanskaite-Banevi\u010d","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R\u016bta","family":"Petraitien\u0117","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramun\u0117","family":"Grigalevi\u010di\u016bt\u0117","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ethan","family":"Naing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vytautas","family":"Mickevi\u010dius","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergey","family":"Belyakov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vidmantas","family":"Petraitis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"issue":"5","key":"pone.0311715.ref001","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.mcna.2018.04.005","article-title":"Antimicrobial resistance: an antimicrobial\/diagnostic stewardship and infection prevention approach","volume":"102","author":"EJ Septimus","year":"2018","journal-title":"Med Clin North Am"},{"issue":"12","key":"pone.0311715.ref002","doi-asserted-by":"crossref","DOI":"10.15252\/embr.202051034","article-title":"Antibiotic resistance and persistence-Implications for human health and treatment perspectives","volume":"21","author":"M Huemer","year":"2020","journal-title":"EMBO Rep"},{"issue":"5","key":"pone.0311715.ref003","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.mcna.2018.05.005","article-title":"Antimicrobial stewardship in community hospitals","volume":"102","author":"WR Buckel","year":"2018","journal-title":"Med Clin North Am"},{"issue":"3","key":"pone.0311715.ref004","article-title":"Antimicrobial Resistance in ESKAPE Pathogens","volume":"33","author":"DMP De Oliveira","year":"2020","journal-title":"Clin Microbiol Rev"},{"key":"pone.0311715.ref005","doi-asserted-by":"crossref","first-page":"539","DOI":"10.3389\/fmicb.2019.00539","article-title":"Emerging strategies to combat ESKAPE pathogens in the era of antimicrobial resistance: a review","volume":"10","author":"MS Mulani","year":"2019","journal-title":"Front Microbiol"},{"issue":"11","key":"pone.0311715.ref006","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1017\/ice.2021.457","article-title":"Discontinuing MRSA and VRE contact precautions: defining hospital characteristics and infection prevention practices predicting safe de-escalation","volume":"43","author":"EM Martin","year":"2022","journal-title":"Infect Control Hosp Epidemiol"},{"key":"pone.0311715.ref007","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1186\/1471-2334-14-177","article-title":"Natural history of colonization with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE): a systematic review","volume":"14","author":"ES Shenoy","year":"2014","journal-title":"BMC Infect Dis"},{"key":"pone.0311715.ref008","doi-asserted-by":"crossref","first-page":"116401","DOI":"10.1016\/j.ejmech.2024.116401","article-title":"Structure optimizing of flavonoids against both MRSA and VRE","volume":"271","author":"MZ Wei","year":"2024","journal-title":"Eur J Med Chem"},{"issue":"3","key":"pone.0311715.ref009","doi-asserted-by":"crossref","first-page":"126","DOI":"10.5694\/mja2.50218","article-title":"Reduced VRE and MRSA colonisation and infection following sustained reduction in broad spectrum antibiotic use in a large tertiary hospital","volume":"211","author":"JK Ferguson","year":"2019","journal-title":"Med J Aust"},{"issue":"4","key":"pone.0311715.ref010","doi-asserted-by":"crossref","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":"4","key":"pone.0311715.ref011","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":"NA Turner","year":"2019","journal-title":"Nat Rev Microbiol"},{"key":"pone.0311715.ref012","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/978-1-4939-9849-4_16","article-title":"Methicillin-resistant Staphylococcus aureus infection and treatment options","volume":"2069","author":"SJ Chalmers","year":"2020","journal-title":"Methods Mol Biol"},{"issue":"1","key":"pone.0311715.ref013","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s13756-023-01278-0","article-title":"Vancomycin-resistant enterococci (VRE) in hospital settings across European borders: a scoping review comparing the epidemiology in the Netherlands and Germany","volume":"12","author":"C Cimen","year":"2023","journal-title":"Antimicrob Resist Infect Control"},{"issue":"4","key":"pone.0311715.ref014","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.idc.2016.07.009","article-title":"Vancomycin-resistant enterococci: epidemiology, infection prevention, and control","volume":"30","author":"K Reyes","year":"2016","journal-title":"Infect Dis Clin North Am"},{"issue":"10","key":"pone.0311715.ref015","doi-asserted-by":"crossref","first-page":"2718","DOI":"10.1093\/jac\/dkv185","article-title":"Epidemiology and molecular typing of VRE bloodstream isolates in an Irish tertiary care hospital","volume":"70","author":"L Ryan","year":"2015","journal-title":"J Antimicrob Chemother"},{"key":"pone.0311715.ref016","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1146\/annurev-biochem-060614-034516","article-title":"Mechanisms of methicillin resistance in Staphylococcus aureus","volume":"84","author":"SJ Peacock","year":"2015","journal-title":"Annu Rev Biochem"},{"issue":"6","key":"pone.0311715.ref017","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1007\/s00284-021-02442-8","article-title":"Antibiotic resistance crisis: an update on antagonistic interactions between probiotics and methicillin-resistant Staphylococcus aureus (MRSA)","volume":"78","author":"BH Nataraj","year":"2021","journal-title":"Curr Microbiol"},{"issue":"27","key":"pone.0311715.ref018","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.2174\/1568026621666211004093647","article-title":"Aminoglycosides with anti-MRSA activity: a concise review","volume":"21","author":"CJ Yao","year":"2021","journal-title":"Curr Top Med Chem"},{"issue":"1","key":"pone.0311715.ref019","doi-asserted-by":"crossref","first-page":"3970","DOI":"10.1038\/s41467-020-17735-y","article-title":"Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates","volume":"11","author":"A Papkou","year":"2020","journal-title":"Nat Commun"},{"issue":"4","key":"pone.0311715.ref020","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/j.idc.2020.08.004","article-title":"Resistance in vancomycin-resistant enterococci","volume":"34","author":"WR Miller","year":"2020","journal-title":"Infect Dis Clin North Am"},{"key":"pone.0311715.ref021","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.drup.2018.10.002","article-title":"Update on prevalence and mechanisms of resistance to linezolid, tigecycline and daptomycin in enterococci in Europe: Towards a common nomenclature","volume":"40","author":"JK Bender","year":"2018","journal-title":"Drug Resist Updat"},{"key":"pone.0311715.ref022","article-title":"The threat of vancomycin resistance","volume":"106","author":"TM Perl","year":"1999","journal-title":"Am J Med"},{"key":"pone.0311715.ref023","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.ejmech.2012.09.048","article-title":"Anticancer activity of small amphipathic \u03b2\u00b2,\u00b2-amino acid derivatives","volume":"58","author":"T Hansen","year":"2012","journal-title":"Eur J Med Chem"},{"key":"pone.0311715.ref024","doi-asserted-by":"crossref","first-page":"114229","DOI":"10.1016\/j.ejmech.2022.114229","article-title":"Structure-activity relationship studies on O-alkylamino-tethered salicylamide derivatives with various amino acid linkers as potent anticancer agents","volume":"234","author":"J Xu","year":"2022","journal-title":"Eur J Med Chem"},{"issue":"3","key":"pone.0311715.ref025","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1021\/jm101327d","article-title":"Synthesis of cationic antimicrobial \u03b2(2,2)-amino acid derivatives with potential for oral administration","volume":"54","author":"T Hansen","year":"2011","journal-title":"J Med Chem"},{"issue":"2","key":"pone.0311715.ref026","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1159\/000521098","article-title":"Synthesis and antimicrobial evaluation of amino acid naphthoquinone derivatives as potential antibacterial agents","volume":"67","author":"LI L\u00f3pez-L\u00f3pez","year":"2022","journal-title":"Chemotherapy"},{"issue":"9","key":"pone.0311715.ref027","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1080\/14656566.2018.1479397","article-title":"Combatting resistant enterococcal infections: a pharmacotherapy review","volume":"19","author":"NJ Mercuro","year":"2018","journal-title":"Expert Opin Pharmacother"},{"issue":"2","key":"pone.0311715.ref028","doi-asserted-by":"crossref","first-page":"193","DOI":"10.3390\/antibiotics13020193","article-title":"Synthesis of 3-((4-Hydroxyphenyl)amino)propanoic Acid Derivatives as Promising Scaffolds for the Development of Antimicrobial Candidates Targeting Multidrug-Resistant Bacterial and Fungal Pathogens","volume":"13","author":"P Kavaliauskas","year":"2024","journal-title":"Antibiotics (Basel)"},{"issue":"11","key":"pone.0311715.ref029","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.01168-21","article-title":"Pharmacokinetics, tissue distribution, and efficacy of VIO-001 (meropenem\/piperacillin\/tazobactam) for treatment of methicillin-resistant Staphylococcus aureus bacteremia in immunocompetent rabbits with chronic indwelling vascular catheters","volume":"65","author":"V Petraitis","year":"2021","journal-title":"Antimicrob Agents Chemother"},{"key":"pone.0311715.ref030","volume-title":"Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. CLSI document M07-A8","author":"Clinical and Laboratory Standards Institute","year":"2009"},{"issue":"13","key":"pone.0311715.ref031","doi-asserted-by":"crossref","first-page":"3125","DOI":"10.3390\/molecules29133125","article-title":"Identification of 3-((4-hydroxyphenyl)amino)propanoic acid derivatives as anticancer candidates with promising antioxidant properties","volume":"29","author":"P Kavaliauskas","year":"2024","journal-title":"Molecules"},{"key":"pone.0311715.ref032","doi-asserted-by":"crossref","first-page":"105214","DOI":"10.1016\/j.bioorg.2021.105214","article-title":"Evaluation of N-aryl-\u03b2-alanine derivatives as anticancer agents in triple-negative breast cancer and glioblastoma in vitro models","volume":"115","author":"M \u017dukauskas","year":"2021","journal-title":"Bioorg Chem"},{"issue":"2","key":"pone.0311715.ref033","doi-asserted-by":"crossref","first-page":"438","DOI":"10.3390\/molecules26020438","article-title":"Selected \u03b22-, \u03b23- and \u03b22,3-amino acid heterocyclic derivatives and their biological perspective","volume":"26","author":"U B\u0105chor","year":"2021","journal-title":"Molecules"},{"issue":"2","key":"pone.0311715.ref034","doi-asserted-by":"crossref","first-page":"299","DOI":"10.3390\/ph16020299","article-title":"Nitrogen containing heterocycles as anticancer agents: a medicinal chemistry perspective","volume":"16","author":"A Kumar","year":"2023","journal-title":"Pharmaceuticals (Basel)"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0311715","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T17:33:31Z","timestamp":1749749611000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0311715"}},"subtitle":[],"editor":[{"given":"Wagdy M.","family":"Eldehna","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,6,12]]},"references-count":34,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,12]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0311715","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,12]]}}}