Peptide/β-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci: Influence of Hydrophobicity and Structural Features on Antibacterial and Hemolytic Properties

Infections with enterococci are challenging to treat due to intrinsic resistance to several antibiotics. Especially vancomycin-resistant and are of considerable concern with a limited number of efficacious therapeutics available. From an initial screening of 20 peptidomimetics, 11 stable peptide/β-peptoid hybrids were found to have antibacterial activity against eight and isolates. Microbiological characterization comprised determination of minimal inhibitory concentrations (MICs), probing of synergy with antibiotics in a checkerboard assay, time-kill studies, as well as assessment of membrane integrity. isolates proved more susceptible than isolates, and no differences in susceptibility between the vancomycin-resistant (VRE) and -susceptible isolates were observed. A test of three peptidomimetics (Ac-[hArg-βNsce] -NH , Ac-[hArg-βNsce-Lys-βNspe] -NH and Oct-[Lys-βNspe] -NH ) in combination with conventional antibiotics (vancomycin, gentamicin, ciprofloxacin, linezolid, rifampicin or azithromycin) revealed no synergy. The same three potent analogues were found to have a bactericidal effect with a membrane-disruptive mode of action. Peptidomimetics Ac-[hArg-βNsce-Lys-βNspe] -NH and Oct-[Lys-βNspe] -NH with low MIC values (in the ranges 2-8 µg/mL and 4-16 µg/mL against and , respectively) and displaying weak cytotoxic properties (i.e.,