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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. [Display omitted] • Molecular simplification-guided design of AlkylGuanidinoUreas (AGUs) to explore SAR. • AGUs show potent antibacterial activity through bactericidal effect. • Membrane-based MoA investigation via membrane models by LUVs, modified PAMPA, and MD. • Cell-based bacterial permeabilization assays confirm a membrane-disrupting behavior. • Simplified derivative 8 emerges as a good candidate for further studies. [ABSTRACT FROM AUTHOR]