<i>N</i> -(ω-Guanidinoalkyl)amides of Eremomycin: New Type of Glycopeptides with High Potency against Planktonic Forms and Biofilms of Resistant Bacteria

The rise of multidrug-resistant Gram-positive pathogens and the persistence of biofilm-associated infections present major challenges for current antimicrobial therapies. In response, we developed a novel series of eremomycin derivatives by introducing ω-guanidine-containing alkyl substituents at the <i>C</i>-terminal carboxyl group. <i>N</i>-(2-Guanidinoethyl)amide of eremomycin (<b>12a</b>) exhibited superior in vitro activity against both vancomycin-sensitive and -resistant strains, including VRE and MRSE, and showed enhanced potency compared to vancomycin, telavancin, and previously reported eremomycin analogs without hemolytic or cytotoxic effects. The compound retained its bactericidal activity in biofilms and, unlike vancomycin, did not stimulate biofilm formation at subinhibitory concentrations. Physicochemical characterization was performed by 2D NMR and high-resolution mass spectrometry, verifying the integrity and proposed chemical structures of the new derivatives. In vivo evaluation in a murine sepsis model demonstrated that compound <b>12a</b> had an ED₅₀ value 14 times lower than that of vancomycin, highlighting its strong therapeutic potential. These findings suggest that guanidine-functionalized eremomycin amides represent a promising new class of glycopeptide antibiotics capable of addressing both resistance and biofilm-related challenges.