title: Mycobacterium tuberculosis gyrase inhibitors as a new class of antitubercular drugs.
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.
authors.affiliation: Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain.
authors.forename: Delia
authors.initials: D
authors.lastname: Blanco
authors.affiliation: Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain esther.x.perez-herran@gsk.com monica.i.cacho@gsk.com.
authors.forename: Esther
authors.initials: E
authors.lastname: Perez-Herran
authors.affiliation: Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain esther.x.perez-herran@gsk.com monica.i.cacho@gsk.com.
authors.forename: Mónica
authors.initials: M
authors.lastname: Cacho
authors.affiliation: Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Ballell
authors.affiliation: Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Castro
authors.affiliation: Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: González Del Río
authors.affiliation: Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Lavandera
authors.affiliation: Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain.
authors.forename: Modesto J
authors.initials: MJ
authors.lastname: Remuiñán
authors.affiliation: Antiviral DPU, Infectious Disease Therapeutic Area Unit, GSK, Research Triangle Park, North Carolina, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Richards
authors.affiliation: Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Rullas
authors.affiliation: Molecular Discovery Research, GSK, Tres Cantos, Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Vázquez-Muñiz
authors.affiliation: TPV, RD Platform Technology & Science, GSK, Research Triangle Park, North Carolina, USA.
authors.forename: Ermias
authors.initials: E
authors.lastname: Woldu
authors.affiliation: Molecular Discovery Research, GSK, Tres Cantos, Madrid, Spain.
authors.forename: María Cleofé
authors.initials: MC
authors.lastname: Zapatero-González
authors.affiliation: Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Mendoza
authors.affiliation: Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Barros
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009163:Mycobacterium bovis / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; D059004:Topoisomerase I Inhibitors