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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Jun 2

PMID 34070683

Citations 4

Authors

Martin Vestergaard

Bolette Skive

Ilona Domraceva

Hanne Ingmer

Henrik Franzyk

Affiliations

Soon will be listed here.

Abstract

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., <10% hemolysis at a ~100-fold higher concentration than their MICs; IC values of 73 and 41 µg/mL, respectively, against HepG2 cells) were identified as promising starting points for further optimization studies.

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References

Niu Y, Wu H, Li Y, Hu Y, Padhee S, Li Q . AApeptides as a new class of antimicrobial agents. Org Biomol Chem. 2013; 11(26):4283-90. DOI: 10.1039/c3ob40444g. View

Vlieghe P, Lisowski V, Martinez J, Khrestchatisky M . Synthetic therapeutic peptides: science and market. Drug Discov Today. 2009; 15(1-2):40-56. DOI: 10.1016/j.drudis.2009.10.009. View

Vehreschild M, Haverkamp M, Biehl L, Lemmen S, Fatkenheuer G . Vancomycin-resistant enterococci (VRE): a reason to isolate?. Infection. 2018; 47(1):7-11. DOI: 10.1007/s15010-018-1202-9. View

Chow J . Aminoglycoside resistance in enterococci. Clin Infect Dis. 2000; 31(2):586-9. DOI: 10.1086/313949. View

Odds F . Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother. 2003; 52(1):1. DOI: 10.1093/jac/dkg301. View

Frederiksen N, Hansen P, Zabicka D, Tomczak M, Urbas M, Domraceva I . Alternating Cationic-Hydrophobic Peptide/Peptoid Hybrids: Influence of Hydrophobicity on Antibacterial Activity and Cell Selectivity. ChemMedChem. 2020; 15(24):2544-2561. DOI: 10.1002/cmdc.202000526. View

Skovbakke S, Larsen C, Heegaard P, Moesby L, Franzyk H . Lipidated α-peptide/β-peptoid hybrids with potent anti-inflammatory activity. J Med Chem. 2014; 58(2):801-13. DOI: 10.1021/jm501341h. View

Jahnsen R, Haney E, Franzyk H, Hancock R . Characterization of a proteolytically stable multifunctional host defense peptidomimetic. Chem Biol. 2013; 20(10):1286-95. DOI: 10.1016/j.chembiol.2013.09.007. View

Bychowska A, Theilacker C, Czerwicka M, Marszewska K, Huebner J, Holst O . Chemical structure of wall teichoic acid isolated from Enterococcus faecium strain U0317. Carbohydr Res. 2011; 346(17):2816-9. DOI: 10.1016/j.carres.2011.09.026. View

10.

Jahnsen R, Sandberg-Schaal A, Frimodt-Moller N, Nielsen H, Franzyk H . End group modification: Efficient tool for improving activity of antimicrobial peptide analogues towards Gram-positive bacteria. Eur J Pharm Biopharm. 2015; 95(Pt A):40-6. DOI: 10.1016/j.ejpb.2015.01.013. View

11.

Miller W, Munita J, Arias C . Mechanisms of antibiotic resistance in enterococci. Expert Rev Anti Infect Ther. 2014; 12(10):1221-36. PMC: 4433168. DOI: 10.1586/14787210.2014.956092. View

12.

Magana M, Pushpanathan M, Santos A, Leanse L, Fernandez M, Ioannidis A . The value of antimicrobial peptides in the age of resistance. Lancet Infect Dis. 2020; 20(9):e216-e230. DOI: 10.1016/S1473-3099(20)30327-3. View

13.

Stiefel P, Schmidt-Emrich S, Maniura-Weber K, Ren Q . Critical aspects of using bacterial cell viability assays with the fluorophores SYTO9 and propidium iodide. BMC Microbiol. 2015; 15:36. PMC: 4337318. DOI: 10.1186/s12866-015-0376-x. View

14.

Liu Y, Knapp K, Yang L, Molin S, Franzyk H, Folkesson A . High in vitro antimicrobial activity of β-peptoid-peptide hybrid oligomers against planktonic and biofilm cultures of Staphylococcus epidermidis. Int J Antimicrob Agents. 2012; 41(1):20-7. DOI: 10.1016/j.ijantimicag.2012.09.014. View

15.

Baker K, Jana B, Hansen A, Nielsen H, Franzyk H, Guardabassi L . Repurposing Azithromycin and Rifampicin Against Gram-Negative Pathogens by Combination With Peptidomimetics. Front Cell Infect Microbiol. 2019; 9:236. PMC: 6615261. DOI: 10.3389/fcimb.2019.00236. View

16.

Williamson R, Le Bouguenec C, Gutmann L, Horaud T . One or two low affinity penicillin-binding proteins may be responsible for the range of susceptibility of Enterococcus faecium to benzylpenicillin. J Gen Microbiol. 1985; 131(8):1933-40. DOI: 10.1099/00221287-131-8-1933. View

17.

Chongsiriwatana N, Patch J, Czyzewski A, Dohm M, Ivankin A, Gidalevitz D . Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides. Proc Natl Acad Sci U S A. 2008; 105(8):2794-9. PMC: 2268539. DOI: 10.1073/pnas.0708254105. View

18.

Frederiksen N, Hansen P, Bjorkling F, Franzyk H . Peptide/Peptoid Hybrid Oligomers: The Influence of Hydrophobicity and Relative Side-Chain Length on Antibacterial Activity and Cell Selectivity. Molecules. 2019; 24(24). PMC: 6943742. DOI: 10.3390/molecules24244429. View

19.

Holdfeldt A, Skovbakke S, Winther M, Gabl M, Nielsen C, Perez-Gassol I . The Lipidated Peptidomimetic Lau-((S)-Aoc)-(Lys-βNphe)6-NH2 Is a Novel Formyl Peptide Receptor 2 Agonist That Activates Both Human and Mouse Neutrophil NADPH Oxidase. J Biol Chem. 2016; 291(38):19888-99. PMC: 5025677. DOI: 10.1074/jbc.M116.736850. View

20.

Lewis K . Platforms for antibiotic discovery. Nat Rev Drug Discov. 2013; 12(5):371-87. DOI: 10.1038/nrd3975. View