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

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

doi:10.1016/j.ejmech.2022.114158

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

Eur J Med Chem. 2022 Mar 5:231:114158. doi: 10.1016/j.ejmech.2022.114158. Epub 2022 Jan 29.

Authors

Affiliations

¹ Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100, Siena, Italy. Electronic address: [email protected].
² Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100, Siena, Italy.
³ Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
⁴ Dipartimento di Biotecnologie Mediche, University of Siena, I-53100, Siena, Italy.
⁵ Department of Science, Roma Tre University, Viale G. Marconi 446, 00146, Roma, Italy.
⁶ Department of Science, Roma Tre University, Viale G. Marconi 446, 00146, Roma, Italy; Fondazione Santa Lucia IRCCS, Roma, Italy.
⁷ Department of Ecological and Biological Sciences, University of Tuscia, Largo Università s.n.c., I-01100, Viterbo, Italy.
⁸ 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.
⁹ Dipartimento di Biotecnologie Mediche, University of Siena, I-53100, Siena, Italy; Lead Discovery Siena s.r.l., Via Vittorio Alfieri 31, I-53019, Castelnuovo Berardenga, Italy.
¹⁰ Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100, Siena, Italy. Electronic address: [email protected].

PMID: 35168113
DOI: 10.1016/j.ejmech.2022.114158

Abstract

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.

Keywords: Antibacterials; Confocal microscopy; Guanidine; Membrane model simulation; Molecular simplification; Permeabilization assays; Propidium iodide; Urea.

MeSH terms

Anti-Bacterial Agents* / chemistry
Anti-Bacterial Agents* / pharmacology
Microbial Sensitivity Tests
Urea* / pharmacology

Substances

Anti-Bacterial Agents
Urea