RT Journal Article
T1 New alkaloid antibiotics that target the DNA topoisomerase I of Streptococcus pneumoniae
A1 García Esteban, María Teresa
A1 Blázquez, María Amparo
A1 Ferrándiz, María José
A1 Sanz, María Jesús
A1 Silva Martín, Noella
A1 Hermoso, Juan Antonio
A1 G. de la Campa, Adela
AB Streptococcus pneumoniae has two type II DNA-topoisomerases (DNA-gyrase and DNA topoisomerase IV) and a single type I enzyme (DNA-topoisomerase I, TopA), as demonstrated here. Although fluoroquinolones target type II enzymes, antibiotics efficiently targeting TopA have not yet been reported. Eighteen alkaloids (seven aporphine and 11 phenanthrenes) were semisynthesized from boldine and used to test inhibition both of TopA activity and of cell growth. Two phenanthrenes (seconeolitsine and N-methyl-seconeolitsine) effectively inhibited both TopA activity and cell growth at equivalent concentrations (∼17 μm). Evidence for in vivo TopA targeting by seconeolitsine was provided by the protection of growth inhibition in a S. pneumoniae culture in which the enzyme was overproduced. Additionally, hypernegative supercoiling was observed in an internal plasmid after drug treatment. Furthermore, a model of pneumococcal TopA was made based on the crystal structure of Escherichia coli TopA. Docking calculations indicated strong interactions of the alkaloids with the nucleotide-binding site in the closed protein conformation, which correlated with their inhibitory effect. Finally, although seconeolitsine and N-methyl-seconeolitsine inhibited TopA and bacterial growth, they did not affect human cell viability. Therefore, these new alkaloids can be envisaged as new therapeutic candidates for the treatment of S. pneumoniae infections resistant to other antibiotics.
PB Elsevier
SN 0021-9258
YR 2011
FD 2011-02-25
LK https://hdl.handle.net/20.500.14352/125406
UL https://hdl.handle.net/20.500.14352/125406
LA eng
NO García, M. T., Blázquez, M. A., Ferrándiz, M. J., Sanz, M. J. S., Silva-Martín, N., Hermoso, J. A., & De La Campa, A. G. (2011). New alkaloid antibiotics that target the DNA topoisomerase I of Streptococcus pneumoniae. Journal of Biological Chemistry, 286(8), 6402-6413. https://doi.org/10.1074/JBC.M110.148148
DS Docta Complutense
RD 17 dic 2025