{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T11:03:22Z","timestamp":1780484602124,"version":"3.54.1"},"reference-count":35,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,2,17]],"date-time":"2024-02-17T00:00:00Z","timestamp":1708128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100016248","name":"Kaunas University of Technology","doi-asserted-by":"publisher","award":["The Doctoral Fund of Kaunas University of Technology No. A-410, approved 26 June 2019."],"award-info":[{"award-number":["The Doctoral Fund of Kaunas University of Technology No. A-410, approved 26 June 2019."]}],"id":[{"id":"10.13039\/501100016248","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Infections caused by multidrug-resistant bacterial and fungal pathogens represent a significant global health concern, contributing to increased morbidity and mortality rates. Therefore, it is crucial to develop novel compounds targeting drug-resistant microbial strains. Herein, we report the synthesis of amino acid derivatives bearing an incorporated 4-hydroxyphenyl moiety with various substitutions. The resultant novel 3-((4-hydroxyphenyl)amino)propanoic acid derivatives 2\u201337 exhibited structure-dependent antimicrobial activity against both ESKAPE group bacteria and drug-resistant Candida species. Furthermore, these derivatives demonstrated substantial activity against Candida auris, with minimum inhibitory concentrations ranging from 0.5 to 64 \u00b5g\/mL. Hydrazones 14\u201316, containing heterocyclic substituents, showed the most potent and broad-spectrum antimicrobial activity. This activity extended to methicillin-resistant Staphylococcus aureus (MRSA) with MIC values ranging from 1 to 8 \u00b5g\/mL, vancomycin-resistant Enterococcus faecalis (0.5\u20132 \u00b5g\/mL), Gram-negative pathogens (MIC 8\u201364 \u00b5g\/mL), and drug-resistant Candida species (MIC 8\u201364 \u00b5g\/mL), including Candida auris. Collectively, these findings underscore the potential utility of the novel 3-((4-hydroxyphenyl)amino)propanoic acid scaffold for further development as a foundational platform for novel antimicrobial agents targeting emerging and drug-resistant bacterial and fungal pathogens.<\/jats:p>","DOI":"10.3390\/antibiotics13020193","type":"journal-article","created":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T05:39:56Z","timestamp":1708321196000},"page":"193","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"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"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0237-9088","authenticated-orcid":false,"given":"Povilas","family":"Kavaliauskas","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry, Kaunas University of Technology, Radvilenu rd. 19, LT-50254 Kaunas, Lithuania"},{"name":"Biological Research Center, Lithuanian University of Health Sciences, Tilzes Street 18, LT-47181 Kaunas, Lithuania"},{"name":"Joan and Sanford I. Weill Department of Medicine, Weill Cornell University, 1300 York Avenue, New York, NY 10065, USA"},{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201, USA"},{"name":"Institute of Infectious Diseases and Pathogenic Microbiology, Birstono Street 38A, LT-59116 Prienai, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birut\u0117","family":"Grybait\u0117","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Kaunas University of Technology, Radvilenu rd. 19, LT-50254 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birut\u0117","family":"Sapijanskait\u0117-Banevi\u010d","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Kaunas University of Technology, Radvilenu rd. 19, LT-50254 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Vaickelionien\u0117","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Kaunas University of Technology, Radvilenu rd. 19, LT-50254 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6811-4467","authenticated-orcid":false,"given":"Vidmantas","family":"Petraitis","sequence":"additional","affiliation":[{"name":"Biological Research Center, Lithuanian University of Health Sciences, Tilzes Street 18, LT-47181 Kaunas, Lithuania"},{"name":"Joan and Sanford I. Weill Department of Medicine, Weill Cornell University, 1300 York Avenue, New York, NY 10065, USA"},{"name":"Institute of Infectious Diseases and Pathogenic Microbiology, Birstono Street 38A, LT-59116 Prienai, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3269-8058","authenticated-orcid":false,"given":"R\u016bta","family":"Petraitien\u0117","sequence":"additional","affiliation":[{"name":"Joan and Sanford I. Weill Department of Medicine, Weill Cornell University, 1300 York Avenue, New York, NY 10065, USA"},{"name":"Institute of Infectious Diseases and Pathogenic Microbiology, Birstono Street 38A, LT-59116 Prienai, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan","family":"Naing","sequence":"additional","affiliation":[{"name":"Joan and Sanford I. Weill Department of Medicine, Weill Cornell University, 1300 York Avenue, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Garcia","sequence":"additional","affiliation":[{"name":"Joan and Sanford I. Weill Department of Medicine, Weill Cornell University, 1300 York Avenue, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramun\u0117","family":"Grigalevi\u010di\u016bt\u0117","sequence":"additional","affiliation":[{"name":"Biological Research Center, Lithuanian University of Health Sciences, Tilzes Street 18, LT-47181 Kaunas, Lithuania"},{"name":"Department of Animal Nutrition, Lithuanian University of Health Sciences, Tilzes Street 18, LT-47181 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9961-2941","authenticated-orcid":false,"given":"Vytautas","family":"Mickevi\u010dius","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Kaunas University of Technology, Radvilenu rd. 19, LT-50254 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,17]]},"reference":[{"key":"ref_1","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":"Septimus","year":"2018","journal-title":"Med. Clin. N. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.mcna.2018.04.004","article-title":"Antimicrobial Stewardship and Antimicrobial Resistance","volume":"102","author":"Rice","year":"2018","journal-title":"Med. Clin. N. Am."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e00181-19","DOI":"10.1128\/CMR.00181-19","article-title":"Antimicrobial Resistance in ESKAPE Pathogens","volume":"33","author":"Forde","year":"2020","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Mulani, M.S., Kamble, E.E., Kumkar, S.N., Tawre, M.S., and Pardesi, K.R. (2019). Emerging Strategies to Combat ESKAPE Pathogens in the Era of Antimicrobial Resistance: A Review. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.00539"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.cmi.2022.10.018","article-title":"Antibiotic heteroresistance in ESKAPE pathogens, from bench to bedside","volume":"29","author":"Roch","year":"2023","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Du, H., Bing, J., Hu, T., Ennis, C.L., Nobile, C.J., and Huang, G. (2020). Candida auris: Epidemiology, biology, antifungal resistance, and virulence. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008921"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.cmi.2019.03.028","article-title":"Resistance of Candida to azoles and echinocandins worldwide","volume":"25","author":"Pristov","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3513","DOI":"10.1002\/cmdc.202100503","article-title":"Amino Acid Based Antimicrobial Agents\u2014Synthesis and Properties","volume":"16","author":"Nowak","year":"2021","journal-title":"ChemMedChem"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1002\/ardp.200900316","article-title":"Original and efficient synthesis of D-cycloserine","volume":"343","author":"Li","year":"2010","journal-title":"Arch. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.jmb.2007.04.048","article-title":"Structural and functional characterization of enantiomeric glutamic acid derivatives as potential transition state analogue inhibitors of MurD ligase","volume":"370","author":"Kotnik","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7486","DOI":"10.1021\/jm800762u","article-title":"Novel naphthalene-N-sulfonyl-D-glutamic acid derivatives as inhibitors of MurD, a key peptidoglycan biosynthesis enzyme","volume":"51","author":"Humljan","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S1074-5521(96)90082-4","article-title":"Synthesis and evaluation of inhibitors of bacterial D-alanine:D-alanine ligases","volume":"3","author":"Ellsworth","year":"1996","journal-title":"Chem. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S1074-5521(00)00052-1","article-title":"Energetic, structural, and antimicrobial analyses of beta-lactam side chain recognition by beta-lactamases","volume":"8","author":"Caselli","year":"2001","journal-title":"Chem. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wamp, S., Rothe, P., Stern, D., Holland, G., D\u00f6hling, J., and Halbedel, S. (2022). MurA escape mutations uncouple peptidoglycan biosynthesis from PrkA signaling. PLoS Pathog., 18.","DOI":"10.1371\/journal.ppat.1010406"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/s41586-023-05750-0","article-title":"Coordination of bacterial cell wall and outer membrane biosynthesis","volume":"615","author":"Hummels","year":"2023","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ctrv.2011.03.001","article-title":"Chemopreventive effects of dietary phytochemicals against cancer invasion and metastasis: Phenolic acids, monophenol, polyphenol, and their derivatives","volume":"38","author":"Weng","year":"2012","journal-title":"Cancer Treat. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"133904","DOI":"10.1016\/j.foodchem.2022.133904","article-title":"Distinctive anti-inflammatory effects of resveratrol, dihydroresveratrol, and 3-(4-hydroxyphenyl)-propionic acid on DSS-induced colitis in pseudo-germ-free mice","volume":"400","author":"Zhang","year":"2023","journal-title":"Food Chem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Berta\u0161i\u016bt\u0117, M., Kavaliauskas, P., Vaickelionien\u0117, R., Grybait\u0117, B., Petraitis, V., Petraitien\u0117, R., Naing, E., Garcia, A., \u0160iug\u017edait\u0117, J., and Lele\u0161ius, R. (2023). Synthesis of 1-(2-Hydroxyphenyl)- and (3,5-Dichloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic Acid Derivatives as Promising Scaffolds for the Development of Novel Antimicrobial and Anticancer Agents. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24097966"},{"key":"ref_19","unstructured":"(1989). Phenol. IARC Monogr. Eval. Carcinog. Risks Hum., 47, 263\u2013287. Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/2699901\/."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7044","DOI":"10.1021\/acs.jmedchem.2c00223","article-title":"Phenols in Pharmaceuticals: Analysis of a Recurring Motif","volume":"65","author":"Scott","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1021\/acs.jafc.7b04418","article-title":"Semisynthetic Phenol Derivatives Obtained from Natural Phenols: Antimicrobial Activity and Molecular Properties","volume":"66","author":"Pinheiro","year":"2018","journal-title":"J. Agric. Food Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1007\/BF00503202","article-title":"Synthesis and transformations of N-(4-hydroxyphenyl)dihydrouracils","volume":"18","author":"Baltrusis","year":"1982","journal-title":"Chem. Heterocycl. Compd."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8234","DOI":"10.1039\/c0cc02502j","article-title":"On-water conjugate additions of anilines","volume":"46","author":"Beattie","year":"2010","journal-title":"Chem. Commun."},{"key":"ref_24","first-page":"139","article-title":"Synthesis and plant growth regulating activity of halo derivatives of 3,3\u2032-(arylimino)dipropanoic acids","volume":"21","author":"Rutkauskas","year":"2010","journal-title":"Chemija"},{"key":"ref_25","first-page":"127","article-title":"Synthesis and structure of N-(4-bromophenyl)-N-carboxyethyl-\u03b2-alanine derivatives","volume":"21","year":"2010","journal-title":"Chemija"},{"key":"ref_26","first-page":"65","article-title":"Synthesis and structure of 3,3\u2032-[(4-alkoxyphenyl)imino]bis(N\u2019-phthaloyl- or N\u2019-benzylidenepropanohydrazide) derivatives","volume":"22","year":"2011","journal-title":"Chemija"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Paulusma, C.C., Lamers, W.H., Broer, S., and van de Graaf, S.F.J. (2022). Amino acid metabolism, transport and signalling in the liver revisited. Biochem. Pharmacol., 201.","DOI":"10.1016\/j.bcp.2022.115074"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ngo, D.H., and Vo, T.S. (2019). An Updated Review on Pharmaceutical Properties of Gamma-Aminobutyric Acid. Molecules, 24.","DOI":"10.3390\/molecules24152678"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Koksharova, O.A., and Safronova, N.A. (2022). Non-Proteinogenic Amino Acid \u03b2-N-Methylamino-L-Alanine (BMAA): Bioactivity and Ecological Significance. Toxins, 14.","DOI":"10.3390\/toxins14080539"},{"key":"ref_30","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","year":"2022","journal-title":"Chemotherapy"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1111\/phpp.12652","article-title":"Evaluation of antimicrobial photodynamic activities of 5-aminolevulinic acid derivatives","volume":"37","author":"Sajjad","year":"2021","journal-title":"Photodermatol. Photoimmunol. Photomed."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3106","DOI":"10.1002\/cmdc.202100397","article-title":"Amino Acid and Peptide-Based Antiviral Agents","volume":"16","author":"Skwarecki","year":"2021","journal-title":"ChemMedChem"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Cui, J., Ji, X., Mi, Y., Miao, Q., Dong, F., Tan, W., and Guo, Z. (2022). Antimicrobial and Antioxidant Activities of N-2-Hydroxypropyltrimethyl Ammonium Chitosan Derivatives Bearing Amino Acid Schiff Bases. Mar. Drugs, 20.","DOI":"10.3390\/md20020086"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"114378","DOI":"10.1016\/j.addr.2022.114378","article-title":"Novel antimicrobial agents for combating antibiotic-resistant bacteria","volume":"187","author":"Chang","year":"2022","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Loyola-Cruz, M.\u00c1., Gonzalez-Avila, L.U., Mart\u00ednez-Trejo, A., Salda\u00f1a-Padilla, A., Hern\u00e1ndez-Cortez, C., Bello-L\u00f3pez, J.M., and Castro-Escarpulli, G. (2023). ESKAPE and Beyond: The Burden of Coinfections in the COVID-19 Pandemic. Pathogens, 12.","DOI":"10.3390\/pathogens12050743"}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/13\/2\/193\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:01:14Z","timestamp":1760104874000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/13\/2\/193"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,17]]},"references-count":35,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["antibiotics13020193"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics13020193","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,17]]}}}