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

Autor: Galano-Frutos JJ; Institute of Chemical Sciences and Technologies 'Giulio Natta' (SCITEC) - CNR, Largo Francesco Vito 1, 00168, Rome, Italy.; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, Zaragoza 50018, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, University of Zaragoza, Zaragoza 50009, Spain., Maity R; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, Zaragoza 50018, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, University of Zaragoza, Zaragoza 50009, Spain., Iguarbe V; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, Zaragoza 50018, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, University of Zaragoza, Zaragoza 50009, Spain., Aínsa JA; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, Zaragoza 50018, Spain.; Departamento de Microbiología, Pediatría, Radiología y Salud Pública, Facultad de Medicina, University of Zaragoza, Zaragoza 50009, Spain.; CIBER de Enfermedades Respiratorias-CIBERES, Instituto de Salud Carlos III, Madrid 28029, Spain., Velázquez-Campoy A; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, Zaragoza 50018, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, University of Zaragoza, Zaragoza 50009, Spain.; Aragon Health Research Institute (IIS Aragón), Zaragoza 50009, Spain.; CIBER de Enfermedades Hepáticas y Digestivas CIBERehd, Instituto de Salud Carlos III, Madrid 28029, Spain., Schaible UE; Cellular Microbiology, Priority Research Area Infections, Research Center Borstel, Leibniz Lung Center, & Leibniz Research Alliance INFECTIONS, Borstel, Germany.; Biochemical Microbiology & Immunochemistry, University of Lübeck, Lübeck, Germany.; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Borstel Germany., Mamat U; Cellular Microbiology, Priority Research Area Infections, Research Center Borstel, Leibniz Lung Center, & Leibniz Research Alliance INFECTIONS, Borstel, Germany., Sancho J; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, Zaragoza 50018, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, University of Zaragoza, Zaragoza 50009, Spain.; Aragon Health Research Institute (IIS Aragón), Zaragoza 50009, Spain.
Jazyk: angličtina
Zdroj: Heliyon [Heliyon] 2024 Mar 22; Vol. 10 (7), pp. e27982. Date of Electronic Publication: 2024 Mar 22 (Print Publication: 2024).
DOI: 10.1016/j.heliyon.2024.e27982
Abstrakt: 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 K d . 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.
Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(© 2024 The Authors.)
Databáze: MEDLINE
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