A novel and concise approach to rare 2,3,5-triamino-imidazole scaffolds via Ni-catalyzed coupling of alkylisocyanides and N,N′-diarylguanidines has been developed. This reaction features include mild conditions (thermal or visible light activation), a wide substrate scope, and high efficiency. The coupling proceeds through a NiII/NiIV catalytic cycle, involving two-electron aerobic oxidation and the sequential insertion of two isocyanide units into Ni−N bonds.Testing these compounds against pathogens of the ESKAPE panel showed their high activity with a minimum inhibitory concentration down to 0.38 μg/mL.