TY - JOUR

T1 - Peptide/β-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci

T2 - Influence of Hydrophobicity and Structural Features on Antibacterial and Hemolytic Properties

AU - Vestergaard, Martin

AU - Skive, Bolette

AU - Domraceva, Ilona

AU - Ingmer, Hanne

AU - Franzyk, Henrik

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.3390/ijms22115617

DO - 10.3390/ijms22115617

M3 - Journal article

C2 - 34070683

VL - 22

JO - International Journal of Molecular Sciences (CD-ROM)

JF - International Journal of Molecular Sciences (CD-ROM)

SN - 1424-6783

IS - 11

M1 - 5617

ER -