Peptide/β-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci: Influence of Hydrophobicity and...

Area of Science:

• Microbiology
• Medicinal Chemistry
• Drug Discovery

Background:

• Enterococcal infections pose treatment challenges due to intrinsic antibiotic resistance.
• Vancomycin-resistant Enterococcus faecium and Enterococcus faecalis are significant clinical concerns with limited therapeutic options.

Purpose of the Study:

• To identify novel peptidomimetics with antibacterial activity against Enterococcus species.
• To characterize the mechanism of action and potential for synergy with existing antibiotics.

Main Methods:

• Screening of 20 peptidomimetics to identify active compounds against E. faecium and E. faecalis.
• Determination of minimal inhibitory concentrations (MICs), synergy testing, time-kill studies, and membrane integrity assays.
• Evaluation of cytotoxicity against HepG2 cells.

Main Results:

• Eleven stable peptide/β-peptoid hybrids exhibited antibacterial activity against eight E. faecium and E. faecalis isolates.
• E. faecium isolates were more susceptible than E. faecalis; no difference in susceptibility was observed between vancomycin-resistant and -susceptible E. faecium.
• Three potent analogues demonstrated a bactericidal, membrane-disruptive mechanism of action without synergistic effects with conventional antibiotics.
• Two analogues, Ac-[hArg-βNsce-Lys-βNspe]3-NH2 and Oct-[Lys-βNspe]6-NH2, showed low MIC values and weak cytotoxicity, indicating promise for further development.

Conclusions:

• Peptide/β-peptoid hybrids are effective against E. faecium and E. faecalis, including vancomycin-resistant strains.
• These compounds possess a membrane-disruptive mode of action.
• Selected analogues represent promising starting points for developing novel therapeutics against challenging enterococcal infections.