Antibacterials; Confocal microscopy; Guanidine; Membrane model simulation; Molecular simplification; Permeabilization assays; Propidium iodide; Urea; Anti-Bacterial Agents; Microbial Sensitivity Tests; Anti-Bacterial Agents/chemistry; Anti-Bacterial Agents/pharmacology; Urea/pharmacology; Pharmacology; Drug Discovery; Organic Chemistry; General Medicine
Abstract :
[en] 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.
Disciplines :
Microbiology Life sciences: Multidisciplinary, general & others Immunology & infectious disease
Author, co-author :
D'Agostino, Ilaria ; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100, Siena, Italy. Electronic address: ilaria.dagostino91@gmail.com
Ardino, Claudia; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100, Siena, Italy
Poli, Giulio; Department of Pharmacy, University of Pisa, 56126, Pisa, Italy
Sannio, Filomena ; Dipartimento di Biotecnologie Mediche, University of Siena, I-53100, Siena, Italy
Lucidi, Massimiliano ; Department of Science, Roma Tre University, Viale G. Marconi 446, 00146, Roma, Italy
Poggialini, Federica ; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100, Siena, Italy
Visaggio, Daniela ; Department of Science, Roma Tre University, Viale G. Marconi 446, 00146, Roma, Italy, Fondazione Santa Lucia IRCCS, Roma, Italy
Rango, Enrico ; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100, Siena, Italy
Filippi, Silvia ; Department of Ecological and Biological Sciences, University of Tuscia, Largo Università s.n.c., I-01100, Viterbo, Italy
Petricci, Elena; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100, Siena, Italy
Visca, Paolo ; Department of Science, Roma Tre University, Viale G. Marconi 446, 00146, Roma, Italy, Fondazione Santa Lucia IRCCS, Roma, Italy
Botta, Lorenzo; Department of Ecological and Biological Sciences, University of Tuscia, Largo Università s.n.c., I-01100, Viterbo, Italy, Lead Discovery Siena s.r.l., Via Vittorio Alfieri 31, I-53019, Castelnuovo Berardenga, Italy
Docquier, Jean-Denis ; Université de Liège - ULiège > Département des sciences de la vie > Centre d'Ingénierie des Protéines (CIP)
Dreassi, Elena ; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100, Siena, Italy. Electronic address: elena.dreassi@unisi.it
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