RT Journal Article
T1 Effective GTP-replacing FtsZ inhibitors and antibacterial mechanism of action
A1 Artola, Marta
A1 Ruiz Ávila, Laura
A1 Vergonos, Albert
A1 Huecas, Sonia
A1 Araujo Bazán, Lidia
A1 Martín-Fontecha Corrales, María Del Mar
A1 Vázquez Villa, María Del Henar
A1 Turrado, Carlos
A1 Ramírez Aportela, Erney
A1 Hoegl, Annabelle
A1 Nodwell, Matthew
A1 Barasoain, Isabel
A1 Chacón, Pablo
A1 Sieber, Stephan A.
A1 Andreu, Jose M.
A1 López Rodríguez, María Luz
AB Essential cell division protein FtsZ is considered an attractive target in the search for antibacterials with novel mechanisms of action to overcome the resistance problem. FtsZ undergoes GTP-dependent assembly at midcell to form the Z-ring, a dynamic structure that evolves until final constriction of the cell. Therefore, molecules able to inhibit its activity will eventually disrupt bacterial viability. In this work, we report a new series of small molecules able to replace GTP and to specifically inhibit FtsZ, blocking the bacterial division process. These new synthesized inhibitors interact with the GTP-binding site of FtsZ (Kd = 0.4–0.8 μM), display antibacterial activity against Gram-positive pathogenic bacteria, and show selectivity against tubulin. Biphenyl derivative 28 stands out as a potent FtsZ inhibitor (Kd = 0.5 μM) with high antibacterial activity [MIC (MRSA) = 7 μM]. In-depth analysis of the mechanism of action of compounds 22, 28, 33, and 36 has revealed that they act as effective inhibitors of correct FtsZ assembly, blocking bacterial division and thus leading to filamentous undivided cells. These findings provide a compelling rationale for the development of compounds targeting the GTP-binding site as antibacterial agents and open the door to antibiotics with novel mechanisms of action.
PB ACS Publications
SN 1554-8929
YR 2015
FD 2015-03-01
LK https://hdl.handle.net/20.500.14352/114176
UL https://hdl.handle.net/20.500.14352/114176
LA eng
NO Artola, M., Ruiz-Avila, L. B., Vergoñós, A., Huecas, S., Araujo-Bazán, L., Martín-Fontecha, M., Vázquez-Villa, H., Turrado, C., Ramírez-Aportela, E., Hoegl, A., Nodwell, M., Barasoain, I., Chacón, P., Sieber, S. A., Andreu, J. M., López-Rodríguez, M. L. Effective GTP-Replacing FtsZ Inhibitors and Antibacterial Mechanism of Action. ACS Chem. Biol. 2015, 10 (3), 834-843
NO Ministería de Economía y Competetividad
NO Comunidad de Madrid
NO European Social Fundation
DS Docta Complutense
RD 6 abr 2025