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00925njm 22002777a 4500 dc Garcia, Maria Teresa author Blázquez, María Amparo author Ferrandiz-Avellano, Maria-Jose author Sanz, María Jesús author Silva-Martín, Noella author Hermoso, Juan A author de la Campa, Adela G author 2011-02-25 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. J Biol Chem. 2011 Feb 25;286(8):6402-13. doi: 10.1074/jbc.M110.148148. Epub 2010 Dec 17. 10.1074/jbc.M110.148148 1083-351X 0021-9258 The Journal of biological chemistry 21169356 http://hdl.handle.net/20.500.12105/8593 New alkaloid antibiotics that target the DNA topoisomerase I of Streptococcus pneumoniae