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Mycobacterium tuberculosis Gyrase Inhibitors as a New Class of Antitubercular Drugs |
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| Authors: | Delia Blanco Esther Perez-Herran Mónica Cacho Lluís Ballell Julia Castro Rubén González del Río José Luis Lavandera Modesto J. Remui?án Cindy Richards Joaquin Rullas María Jesús Vázquez-Mu?iz Ermias Woldu María Cleofé Zapatero-González I?igo Angulo-Barturen Alfonso Mendoza David Barros |
| Affiliation: | aDiseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain;bAntiviral DPU, Infectious Disease Therapeutic Area Unit, GSK, Research Triangle Park, North Carolina, USA;cMolecular Discovery Research, GSK, Tres Cantos, Madrid, Spain;dTPV, RD Platform Technology & Science, GSK, Research Triangle Park, North Carolina, USA |
| Abstract: | One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkable in vitro and in vivo antitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization. |
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