L-Thyroxine and L-thyroxine-based antimicrobials against Streptococcus pneumoniae and other Gram-positive bacteria

Galano-Frutos, Juan José (Universidad de Zaragoza) ; Maity, Ritwik ; Iguarbe, Verónica (Universidad de Zaragoza) ; Aínsa, José Antonio (Universidad de Zaragoza) ; Velázquez-Campoy, Adrián (Universidad de Zaragoza) ; Schaible, Ulrich E. ; Mamat, Uwe ; Sancho, Javier (Universidad de Zaragoza)

Resumen: 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.

Idioma: Inglés

DOI: 10.1016/j.heliyon.2024.e27982

Año: 2024

Publicado en: Heliyon 10, 7 (2024), e27982 [11 pp.]
ISSN: 2405-8440

Financiación: info:eu-repo/grantAgreement/ES/DGA/E45-23R
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2019-107293GB-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2022-141068NB-I00

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Microbiología (Dpto. Microb.Ped.Radio.Sal.Pú.)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)