Please join us to hear from two esteemed overseas colleagues, Dr Josefine Eilsoe Nielsen - Stanford University, USA (https://bioengineering.stanford.edu/people/josefine-nielsen) and Prof Havard Jenssen - Roskilde University, Denmark (https://forskning.ruc.dk/en/persons/jenssen)
Relevant details are as follows:
Date: Monday 16 May 2022
Time: 1.30pm - 2.30pm
Location: Rupert Myers Theatre, North Wing Rupert Myers Building, Gate 14 Barker Street, Kensington, UNSW Sydney, NSW 2052
Title: “One ellipsoid to control them all — Peptoid anti-infectives that are antibacterial, antiviral, & antifungal”
Infections caused by a variety of microorganisms, including bacteria, viruses and fungi are of increasing global concern, and polymicrobial diseases caused by combinations of microorganisms are recognized with increasing frequency. Yet the clinical pipeline of new antimicrobials is dry, with only 6 innovative antibiotics that address the WHO list of priority pathogens in development in 2019. Antimicrobial peptides (AMPs) with broad-spectrum activity represent a novel source of potential antimicrobials. Yet the clinical development of AMPs as antimicrobial drugs is hampered by a number of factors, especially their enzymatically labile structure. We report here the astonishingly broad-spectrum antimicrobial potential of peptoid mimics of AMPs (sequence-specific N-substituted glycine oligomers), across three different classes of infectious organisms. Peptoids are insensitive to proteases and thus are better drugs than peptides. Our results demonstrate that several peptoids exhibit potent in vitro and in vivo activity against all of the ESKAPE bacterial pathogens, the very resilient M. tuberculosis bacteria, Influenza, HSV-1, and SARS-CoV-2 virus and a range of fungi, making them good drug candidates for treating polymicrobial infections.
We find that some of these peptoids permeabilize membranes even faster than natural AMPs, and act by direct non-specific physical aggregation of intracellular macro-anions, including ribosomes and DNA, resulting in a rapid rigidification of the bacterial cytoplasm. We discuss how and why differing molecular features between different peptoid candidates affects antimicrobial activity and selectivity, specifically, the self-assembly of the most effective peptoids into discrete micellar structures such as ellipsoidal micelles comprising ~100 peptoid molecules per micelle, or helical bundles comprising 2-4 peptoid molecules per bundle. We confirm that these peptoids exhibit no apparent cytotoxicity in vitro with primary human cells at concentrations of up to 256 µg/mL and are well tolerated in vivo, making them exciting drug candidates as a novel class of broad-spectrum anti-infectives.
Dr. Josefine Eilsø Nielsen has a MSc in Pharmacy, and a PhD in biophysical chemistry from the University of Oslo. In her PhD she studied the effect of antimicrobial peptides (AMPs) on the structure and dynamics of lipid membrane systems using small angle X-ray and neutron scattering as well as neutron reflectivity methodology. Currently, Nielsen holds the Novo Nordisk Foundation Stanford Bio-X fellowship, and is affiliated both with Prof. Annelise Barron at Stanford University and Prof. Håvard Jenssen at Roskilde University. Her current project focuses on investigating self-assembly and complexation properties of peptoids and peptides, interesting both for their antimicrobial activity as well as a potential key to understanding pathogenesis of Alzheimer’s disease and Type 2 Diabetes.
Title: "From bio active peptides to peptidomimetics"
Infections caused by a variety of microorganisms, including bacteria, viruses and fungi are of increasing global concern, and polymicrobial diseases caused by combinations of microorganisms are recognized with increasing frequency. Yet the clinical pipeline of new antimicrobials is dry, with only 6 innovative antibiotics that address the WHO list of priority pathogens in development in 2019. Antimicrobial peptides (AMPs) with broad-spectrum activity represent a novel source of potential antimicrobials. We and others have reported on a broad spectrum of these antimicrobial and immune modulating activities, illustrating their potential in a variety of clinical settings, covering direct antibacterial activities, anti-biofilm properties, wound healing, and tissue regeneration, as well as coatings. Yet the clinical development of AMPs as antimicrobial drugs is hampered by a number of factors, especially related to their enzymatically labile structure. Thus, efforts have been made in converting bioactive peptides into more enzymatically stable mimetics without losing their biological activity.
Dr. Håvard Jenssen hold a C.E. in Biotechnology, and a Dr.Sci. in Peptide chemistry, with focus on peptide applications in antiviral drug discovery. His has done a post doc in the lab of Prof. Bob Hancock acquiring skills in computer aided antibacterial peptide design. For the past 12 years he has been leading a peptide drug discovery group at Roskilde University, focusing on anti-bacterial, immune modulating and wound healing peptides and peptidomimetics.