New binding assay developed to identify inhibitors of bacterial cell division with antibacterial properties

A recent publication in the Journal of Medicinal Chemistry by the groups of Drs. José Manuel Andreu and Carlos Fernández-Tornero at Centro de Investigaciones Biológicas Margarita Salas (CSIC), in collaboration with the group of Prof. María L. López-Rodríguez at Universidad Complutense de Madrid, has presented a new binding assay that allows the identification of new ligands of the FtsZ protein which act as inhibitors of bacterial cell division.

Bacterial resistance to antibiotics is one of the greatest threats to global health making it more difficult to treat infections by the loss of efficacy of antibiotics, and highlighting the need for new antibacterial strategies.

FtsZ is an essential protein involved in the bacterial cell division process, where it orchestrates the assembly of the divisome machinery. Bacterial division and FtsZ have been recognized as possible targets for discovering new antibiotics. Moreover, it has been demonstrated that the binding of small molecules to the interdomain cleft of the FtsZ protein impairs its function, eventually inhibiting bacterial division.

Huecas et al. describe the first competitive binding assay for screening FtsZ ligands based on the use of novel high-affinity fluorescent probes addressed to its interdomain cleft. Complementary phenotypic assays and X-ray crystallography have allowed the validation of this screening strategy for the identification of FtsZ inhibitors, characterizing benzamide FtsZ-targeting inhibitors of bacterial division in B. subtilis and methicillin-resistant S. aureus and evaluating their binding affinity.

The methodology presented in the work might facilitate the discovery and validation of new structurally diverse FtsZ allosteric inhibitors leading to more effective antibacterial agents.

Reference: Targeting the FtsZ Allosteric Binding Site with a Novel Fluorescence Polarization Screen, Cytological and Structural Approaches for Antibacterial Discovery. Sonia Huecas, Lidia Araújo-Bazán, Federico M. Ruiz, Laura B. Ruiz-Ávila, R. Fernando Martínez, Andrea Escobar-Peña, Marta Artola, Henar Vázquez-Villa, Mar Martín-Fontecha, Carlos Fernández-Tornero, María L. López-Rodríguez, and José M. Andreu. J. Med. Chem. DOI: 10.1021/acs.jmedchem.0c02207