{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T05:39:48Z","timestamp":1777527588148,"version":"3.51.4"},"reference-count":60,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T00:00:00Z","timestamp":1695168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Catholic University of Cuenca","award":["PICVII19-58"],"award-info":[{"award-number":["PICVII19-58"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>The spread of nosocomial infections caused by antibiotic-resistant Enterococcus faecalis is one of the major threats to global health at present. While aminoglycosides are often used to combat these infections, their effectiveness is reduced by various resistance mechanisms, including aminoglycoside modifying enzymes, and there are currently no drugs to inhibit these enzymes. To address this issue, this study was conducted to identify potential aminoglycoside adjuvants from a database of 462 flavones. The affinity of these molecules with the nucleotide-binding site (NBS) of aminoglycoside phosphotransferase type IIIa of E. faecalis (EfAPH(3\u2019)-IIIa) was evaluated, and the five molecules with the highest binding energies were identified. Of these, four were naphthoflavones, suggesting that their backbone could be useful in designing potential inhibitors. The highest-ranked naphthoflavone, 2-phenyl-4H-benzo[h]chromen-4-one, was modified to generate two new derivatives (ANF2OHC and ANF2OHCC) to interact with the NBS similarly to adenine in ATP. These derivatives showed higher binding free energies, better stability in molecular dynamics analysis and superior pharmacokinetic and toxicological profiles compared to the parent molecule. These findings suggest that these alpha-naphthoflavone derivatives are potential inhibitors of EfAPH(3\u2019)-IIIa and that this core may be a promising scaffold for developing adjuvants that restore the sensitivity of aminoglycosides.<\/jats:p>","DOI":"10.3390\/microorganisms11092351","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T21:47:03Z","timestamp":1695246423000},"page":"2351","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Alpha-Naphthoflavone as a Novel Scaffold for the Design of Potential Inhibitors of the APH(3\u2019)-IIIa Nucleotide-Binding Site of Enterococcus faecalis"],"prefix":"10.3390","volume":"11","author":[{"given":"Juliana Carolina","family":"Amorim","sequence":"first","affiliation":[{"name":"Unidad Acad\u00e9mica de Salud y Bienestar, Universidad Cat\u00f3lica de Cuenca, Av. Las Am\u00e9ricas, Cuenca 010105, Ecuador"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Marcelo","family":"Carpio","sequence":"additional","affiliation":[{"name":"Unidad Acad\u00e9mica de Salud y Bienestar, Universidad Cat\u00f3lica de Cuenca, Av. Las Am\u00e9ricas, Cuenca 010105, Ecuador"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,20]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2014). Antimicrobial Resistance: Global Report on Surveillance, WHO."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e24655","DOI":"10.1002\/jcla.24655","article-title":"Antibiotic resistance: The challenges and some emerging strategies for tackling a global menace","volume":"36","author":"Nwobodo","year":"2022","journal-title":"J. Clin. Lab. 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