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

Martin Vestergaard,Hanne Ingmer,Henrik Franzyk,Ilona Domraceva,Bolette Skive

doi:10.3390/ijms22115617

Abstract

Infections with enterococci are challenging to treat due to intrinsic resistance to several antibiotics. Especially vancomycin-resistant Enterococcus faecium and Enterococcus faecalis 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 E. faecium and E. faecalis 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. E. faecium isolates proved more susceptible than E. faecalis isolates, and no differences in susceptibility between the vancomycin-resistant (VRE) and -susceptible E. faecium isolates were observed. A test of three peptidomimetics (Ac-[hArg-βNsce]6-NH2, Ac-[hArg-βNsce-Lys-βNspe]3-NH2 and Oct-[Lys-βNspe]6-NH2) 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]3-NH2 and Oct-[Lys-βNspe]6-NH2 with low MIC values (in the ranges 2–8 µg/mL and 4–16 µg/mL against E. faecium and E. faecalis, respectively) and displaying weak cytotoxic properties (i.e., <10% hemolysis at a ~100-fold higher concentration than their MICs; IC50 values of 73 and 41 µg/mL, respectively, against HepG2 cells) were identified as promising starting points for further optimization studies.

Highlights

Antibiotics constitute one of the most successful classes of therapeutics in human medicine, and they have significantly reduced the morbidity and mortality caused by bacterial infections during the last century [1]
Our capacity to cure bacterial infections is threatened by the emergence and dissemination of antimicrobial resistance (AMR) [2]
New therapeutics targeting drugresistant Gram-negative bacteria are of highest importance; new therapeutics against certain Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), are urgently needed as well [3,4]

Summary

Introduction

Antibiotics constitute one of the most successful classes of therapeutics in human medicine, and they have significantly reduced the morbidity and mortality caused by bacterial infections during the last century [1]. Priority lists for drug-resistant pathogens, for which new therapeutics are most urgently needed, have been defined by the World Health Organization and the American Centers for Disease Control [3,4]. New therapeutics targeting drugresistant Gram-negative bacteria are of highest importance; new therapeutics against certain Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), are urgently needed as well [3,4]. Enterococci are usually considered to be commensals of the human gastrointestinal tract; upon spreading into the bloodstream, they can cause bacteremia and endocarditis that are associated with high mortality [5,6]. The most important enterococcal species associated with disease in humans are E. faecalis and E. faecium [5,6]

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