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

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.

How Adding Chlorhexidine or Metallic Nanoparticles Affects the Antimicrobial Performance of Calcium Hydroxide Paste as an Intracanal Medication: An In Vitro Study

“…The dosages of CHX incorporated into the CH paste were selected according to the most commonly used concentrations in similar studies [ 13 , 14 , 15 , 18 , 19 , 20 , 22 , 25 ] for comparison purposes. For the metallic salts, in particular the PMNPs, which are still very little studied as intracanal medications, the antimicrobial susceptibilities of E. faecalis and C. albicans were first verified using a standard MIC/MBC determination method (CLSI M07-A8), and the dosages to be tested were selected based on the MICs (0.5×, 1×, and 2×), as previously described [ 50 , 51 , 52 ]. At this first screening stage, copper and zinc (whose MIC values reached or exceeded 3200 mg/L for both E. faecalis and C. albicans ) were excluded.…”

Peptide/β-Peptoid Hybrids with Ultrashort PEG-Like Moieties: Effects on Hydrophobicity, Antibacterial Activity and Hemolytic Properties

“…By contrast, analogs eluting above 44% MeCN were extremely hemolytic. While the present series of compounds (having a hydrophobicity within the narrow range 40.8-42.4% MeCN) comply with these thresholds, a recent study infers that such hydrophobicity thresholds may vary slightly among different structural classes [55].…”

Helical sulfono-γ-AApeptides with predictable functions in protein recognition

“…[8][9][10][11][12] To date, these foldamer systems have been used to mimic various aspects of the folding and organization of natural peptides and proteins. A number of outstanding studies based on unnatural foldamers that have been developed involve b-peptides, 13,14 peptoids, [15][16][17] b-peptoids, 18,19 oligoureas, 20 azapeptides, [21][22][23] and others.…”