Benzamide Derivatives Targeting the Cell Division Protein FtsZ: Modifications of the Linker and the Benzodioxane Scaffold and Their Effects on Antimicrobial Activity

• Main Authors: Valentina Straniero, Lorenzo Suigo, Andrea Casiraghi, Victor Sebastián-Pérez, Martina Hrast, Carlo Zanotto, Irena Zdovc, Carlo De Giuli Morghen, Antonia Radaelli, Ermanno Valoti
• Format: Article
• Language: English
• Published: MDPI AG 2020-04-01
• Series: Antibiotics
• Subjects: cell division protein FtsZ; benzamide; 1,4-benzodioxane; 1,4-benzoxathiane; multi-drug resistant <i>Staphylococcus aureus</i>; <i>Escherichia coli</i> N43
• Online Access: https://www.mdpi.com/2079-6382/9/4/160

Filamentous temperature-sensitive Z (FtsZ) is a prokaryotic protein with an essential role in the bacterial cell division process. It is widely conserved and expressed in both Gram-positive and Gram-negative strains. In the last decade, several research groups have pointed out molecules able to target FtsZ in <i>Staphylococcus aureus</i>, <i>Bacillus subtilis</i> and other Gram-positive strains, with sub-micromolar Minimum Inhibitory Concentrations (MICs). Conversely, no promising derivatives active on Gram-negatives have been found up to now. Here, we report our results on a class of benzamide compounds, which showed comparable inhibitory activities on both <i>S. aureus</i> and <i>Escherichia coli</i> FtsZ, even though they proved to be substrates of <i>E. coli</i> efflux pump AcrAB, thus affecting the antimicrobial activity. These surprising results confirmed how a single molecule can target both species while maintaining potent antimicrobial activity. A further computational study helped us decipher the structural features necessary for broad spectrum activity and assess the drug-like profile and the on-target activity of this family of compounds.