Antibacterial alkylguanidino ureas: Molecular simplification approach, searching for membrane-based MoA.

The ever-faster rise of antimicrobial resistance (AMR) represents a major global Public Health challenge. New chemical entities with innovative Modes of Action (MoAs) are thus desirable. We recently reported the development of a novel class of broad-spectrum bactericidal agents, the AlkylGuanidino Ureas (AGU). Due to their polycationic structure, they likely target bacterial membranes. In order to better understand their MoA, we synthesized a library of AGU derivatives by structural simplification of selected hit compounds and developed specific assays based on membrane models by means of both analytical and computational techniques. Cell-based assays provided experimental evidence that AGUs disrupt bacterial membranes without showing hemolytic behavior. Hence, we herein report a thorough chemical and biological characterization of a new series of AGUs obtained through molecular simplification, allowing the rational design of potent antibacterial compounds active on antibiotic-resistant strains. Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Citation

Ilaria D'Agostino, Claudia Ardino, Giulio Poli, Filomena Sannio, Massimiliano Lucidi, Federica Poggialini, Daniela Visaggio, Enrico Rango, Silvia Filippi, Elena Petricci, Paolo Visca, Lorenzo Botta, Jean-Denis Docquier, Elena Dreassi. Antibacterial alkylguanidino ureas: Molecular simplification approach, searching for membrane-based MoA. European journal of medicinal chemistry. 2022 Mar 05;231:114158

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PMID: 35168113

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