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Effective GTP-replacing FtsZ inhibitors and antibacterial mechanism of action.
ACS Chem Biol. 2015 Mar 20; 10(3):834-43.AC

Abstract

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.

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Authors+Show Affiliations

Artola M
†Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
Ruiz-Avila LB
‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
Vergoñós A
‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
Huecas S
‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
Araujo-Bazán L
‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
Martín-Fontecha M
†Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
Vázquez-Villa H
†Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
Turrado C
†Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
Ramírez-Aportela E
‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain. §Instituto de Química-Física Rocasolano, CSIC, E-28006 Madrid, Spain.
Hoegl A
∥Center for Integrated Protein Science Munich, Technische Universität München, Department of Chemistry, D-85747 Garching, Germany.
Nodwell M
∥Center for Integrated Protein Science Munich, Technische Universität München, Department of Chemistry, D-85747 Garching, Germany.
Barasoain I
‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
Chacón P
§Instituto de Química-Física Rocasolano, CSIC, E-28006 Madrid, Spain.
Sieber SA
∥Center for Integrated Protein Science Munich, Technische Universität München, Department of Chemistry, D-85747 Garching, Germany.
Andreu JM
‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
López-Rodríguez ML
†Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.

MeSH

Anti-Bacterial AgentsBacillus subtilisBacterial ProteinsBinding SitesBiphenyl CompoundsCytoskeletal ProteinsGuanosine TriphosphateKineticsMethicillin-Resistant Staphylococcus aureusMicrobial Sensitivity TestsModels, MolecularNaphthalenesProtein BindingProtein Structure, SecondaryProtein Structure, TertiaryStructure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25486266

Citation

Artola, Marta, et al. "Effective GTP-replacing FtsZ Inhibitors and Antibacterial Mechanism of Action." ACS Chemical Biology, vol. 10, no. 3, 2015, pp. 834-43.
Artola M, Ruiz-Avila LB, Vergoñós A, et al. Effective GTP-replacing FtsZ inhibitors and antibacterial mechanism of action. ACS Chem Biol. 2015;10(3):834-43.
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. (2015). Effective GTP-replacing FtsZ inhibitors and antibacterial mechanism of action. ACS Chemical Biology, 10(3), 834-43. https://doi.org/10.1021/cb500974d
Artola M, et al. Effective GTP-replacing FtsZ Inhibitors and Antibacterial Mechanism of Action. ACS Chem Biol. 2015 Mar 20;10(3):834-43. PubMed PMID: 25486266.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effective GTP-replacing FtsZ inhibitors and antibacterial mechanism of action. AU - Artola,Marta, AU - Ruiz-Avila,Laura B, AU - Vergoñós,Albert, AU - Huecas,Sonia, AU - Araujo-Bazán,Lidia, AU - Martín-Fontecha,Mar, AU - Vázquez-Villa,Henar, AU - Turrado,Carlos, AU - Ramírez-Aportela,Erney, AU - Hoegl,Annabelle, AU - Nodwell,Matthew, AU - Barasoain,Isabel, AU - Chacón,Pablo, AU - Sieber,Stephan A, AU - Andreu,Jose M, AU - López-Rodríguez,María L, Y1 - 2014/12/30/ PY - 2014/12/9/entrez PY - 2014/12/9/pubmed PY - 2015/12/15/medline SP - 834 EP - 43 JF - ACS chemical biology JO - ACS Chem Biol VL - 10 IS - 3 N2 - 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. SN - 1554-8937 UR - https://www.unboundmedicine.com/medline/citation/25486266/Effective_GTP_replacing_FtsZ_inhibitors_and_antibacterial_mechanism_of_action_ DB - PRIME DP - Unbound Medicine ER -