133381 20260217205504.0 doi 10.1016/j.heliyon.2024.e27982 sideral 138072 ART-2024-138072 eng Galano-Frutos, Juan José Universidad de Zaragoza (orcid)0000-0002-1896-7805 L-Thyroxine and L-thyroxine-based antimicrobials against Streptococcus pneumoniae and other Gram-positive bacteria 2024 Access copy available to the general public Unrestricted Objectives: The rise of antibiotic-resistant Streptococcus pneumoniae (Sp) poses a significant global health threat, urging the quest for novel antimicrobial solutions. We have discovered that the human hormone l-thyroxine has antibacterial properties. In order to explore its drugability we perform here the characterization of a series of l-thyroxine analogues and describe the structural determinants influencing their antibacterial efficacy. Method: We performed a high-throughput screening of a library of compounds approved for use in humans, complemented with ITC assays on purified Sp-flavodoxin, to pinpoint molecules binding to this protein. Antimicrobial in vitro susceptibility assays of the hit compound (l-thyroxine) as well as of 13 l-thyroxine analogues were done against a panel of Gram-positive and Gram-negative bacteria. Toxicity of compounds on HepG2 cells was also assessed. A combined structure-activity and computational docking analysis was carried out to uncover functional groups crucial for the antimicrobial potency of these compounds. Results: Human l-thyroxine binds to Sp-flavodoxin, forming a 1:1 complex of low micromolar Kd. While l-thyroxine specifically inhibited Sp growth, some derivatives displayed activity against other Gram-positive bacteria like Staphylococcus aureus and Enterococcus faecalis, while remaining inactive against Gram-negative pathogens. Neither l-thyroxine nor some selected derivatives exhibited toxicity to HepG2 cells. Conclusions: l-thyroxine derivatives targeting bacterial flavodoxins represent a new and promising class of antimicrobials. info:eu-repo/grantAgreement/ES/DGA/E45-23R info:eu-repo/grantAgreement/ES/MICINN/PID2019-107293GB-I00 info:eu-repo/grantAgreement/ES/MICINN/PID2022-141068NB-I00 info:eu-repo/semantics/openAccess by-nc-nd https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es 3.6 2024 MULTIDISCIPLINARY SCIENCES 29 / 136 = 0.213 2024 Q1 T1 0.644 2024 Multidisciplinary 2024 Q1 4.1 2024 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Maity, Ritwik (orcid)0000-0003-4058-2888 Iguarbe, Verónica Universidad de Zaragoza (orcid)0000-0003-1237-6788 Aínsa, José Antonio Universidad de Zaragoza (orcid)0000-0003-2076-844X Velázquez-Campoy, Adrián Universidad de Zaragoza (orcid)0000-0001-5702-4538 Schaible, Ulrich E. Mamat, Uwe Sancho, Javier Universidad de Zaragoza (orcid)0000-0002-2879-9200 1011 630 Universidad de Zaragoza Dpto. Microb.Ped.Radio.Sal.Pú. Área Microbiología 2013 765 Universidad de Zaragoza Dpto. Química Orgánica Área Química Orgánica 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 10, 7 (2024), e27982 [11 pp.] Heliyon Heliyon 2405-8440 4068525 http://zaguan.unizar.es/record/133381/files/texto_completo.pdf Versión publicada 1913557 http://zaguan.unizar.es/record/133381/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:133381 articulos driver 2026-02-17-20:23:02 ARTICLE