Benzamide Derivatives Targeting the Cell Division Protein FtsZ: Modifications of the Linker and the Benzodioxane Scaffold and Their Effects on Antimicrobial Activity
Valentina Straniero,
Lorenzo Suigo,
Andrea Casiraghi,
Victor Sebastián-Pérez,
Martina Hrast,
Carlo Zanotto,
Irena Zdovc,
Carlo De Giuli Morghen,
Antonia Radaelli,
Ermanno Valoti
Affiliations
Valentina Straniero
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Luigi Mangiagalli, 25, 20133 Milano, Italy
Lorenzo Suigo
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Luigi Mangiagalli, 25, 20133 Milano, Italy
Andrea Casiraghi
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Luigi Mangiagalli, 25, 20133 Milano, Italy
Victor Sebastián-Pérez
Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
Martina Hrast
Pharmacy Faculty, University of Ljubljana, Aškerčeva cesta, 7, 1000 Ljubljana, Slovenia
Carlo Zanotto
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Vanvitelli, 32, 20129 Milano, Italy
Irena Zdovc
Veterinary Faculty, University of Ljubljana, Gerbičeva, 60, 1000 Ljubljana, Slovenia
Carlo De Giuli Morghen
Department of Chemical – Pharmaceutical and Biomolecular Technologies, Catholic University “Our Lady of Good Counsel”, Rr. Dritan Hoxha, 1025 Tirana, Albania
Antonia Radaelli
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Vanvitelli, 32, 20129 Milano, Italy
Ermanno Valoti
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Luigi Mangiagalli, 25, 20133 Milano, Italy
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 Staphylococcus aureus, Bacillus subtilis 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 S. aureus and Escherichia coli FtsZ, even though they proved to be substrates of E. coli 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.