000133381 001__ 133381
000133381 005__ 20250923084422.0
000133381 0247_ $$2doi$$a10.1016/j.heliyon.2024.e27982
000133381 0248_ $$2sideral$$a138072
000133381 037__ $$aART-2024-138072
000133381 041__ $$aeng
000133381 100__ $$0(orcid)0000-0002-1896-7805$$aGalano-Frutos, Juan José$$uUniversidad de Zaragoza
000133381 245__ $$aL-Thyroxine and L-thyroxine-based antimicrobials against Streptococcus pneumoniae and other Gram-positive bacteria
000133381 260__ $$c2024
000133381 5060_ $$aAccess copy available to the general public$$fUnrestricted
000133381 5203_ $$aObjectives: 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.
000133381 536__ $$9info:eu-repo/grantAgreement/ES/DGA/E45-23R$$9info:eu-repo/grantAgreement/ES/MICINN/PID2019-107293GB-I00$$9info:eu-repo/grantAgreement/ES/MICINN/PID2022-141068NB-I00
000133381 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
000133381 590__ $$a3.6$$b2024
000133381 592__ $$a0.644$$b2024
000133381 591__ $$aMULTIDISCIPLINARY SCIENCES$$b29 / 135 = 0.215$$c2024$$dQ1$$eT1
000133381 593__ $$aMultidisciplinary$$c2024$$dQ1
000133381 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000133381 700__ $$0(orcid)0000-0003-4058-2888$$aMaity, Ritwik
000133381 700__ $$0(orcid)0000-0003-1237-6788$$aIguarbe, Verónica$$uUniversidad de Zaragoza
000133381 700__ $$0(orcid)0000-0003-2076-844X$$aAínsa, José Antonio$$uUniversidad de Zaragoza
000133381 700__ $$0(orcid)0000-0001-5702-4538$$aVelázquez-Campoy, Adrián$$uUniversidad de Zaragoza
000133381 700__ $$aSchaible, Ulrich E.
000133381 700__ $$aMamat, Uwe
000133381 700__ $$0(orcid)0000-0002-2879-9200$$aSancho, Javier$$uUniversidad de Zaragoza
000133381 7102_ $$11011$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Microbiología
000133381 7102_ $$12013$$2765$$aUniversidad de Zaragoza$$bDpto. Química Orgánica$$cÁrea Química Orgánica
000133381 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000133381 773__ $$g10, 7 (2024), e27982 [11 pp.]$$pHeliyon$$tHeliyon$$x2405-8440
000133381 8564_ $$s4068525$$uhttps://zaguan.unizar.es/record/133381/files/texto_completo.pdf$$yVersión publicada
000133381 8564_ $$s1913557$$uhttps://zaguan.unizar.es/record/133381/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000133381 909CO $$ooai:zaguan.unizar.es:133381$$particulos$$pdriver
000133381 951__ $$a2025-09-22-14:37:05
000133381 980__ $$aARTICLE