Antimicrobial peptides have attracted considerable interest as potential new class of antibiotics against multi-drug resistant bacteria. However, their therapeutic potential is limited, in part due to susceptibility towards enzymatic degradation and low bioavailability. Peptoids (oligomers of N-substituted glycines) demonstrate proteolytic stability and better bioavailability than corresponding peptides while in many cases retaining antibacterial activity. In this study, we synthesized a library of 36 peptoids containing fluorine, chlorine, bromine and iodine atoms, which vary by length and level of halogen substitution in position 4 of the phenyl rings. As we observed a clear correlation between halogenation of an inactive model peptoid and its increased antimicrobial activity, we designed chlorinated and brominated analogues of a known peptoid and its shorter counterpart. Short brominated analogues displayed up to 32-fold increase of the activity against S. aureus and 16- to 64-fold against E. coli and P. aeruginosa alongside reduced cytotoxicity. The biological effect of halogens seems to be linked to the relative hydrophobicity and self-assembly properties of the compounds. By small angle X-ray scattering (SAXS) we have demontrated how the self-assembled structures are dependent on the size of the halogen, degree of substitution and length of the peptoid, and correlated these features to their activity.
#1Charles Chen(MIT: Massachusetts Institute of Technology)H-Index: 29
#1Charles H. Chen(MIT: Massachusetts Institute of Technology)H-Index: 9
Last. Timothy K. Lu(MIT: Massachusetts Institute of Technology)H-Index: 51
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More than 3000 antimicrobial peptides (AMPs) have been discovered, seven of which have been approved by the U.S. Food and Drug Administration (FDA). Now commercialized, these seven peptides have mostly been utilized for topical medications, though some have been injected into the body to treat severe bacterial infections. To understand the translational potential for AMPs, we analyzed FDA-approved drugs in the FDA drug database. We examined their physicochemical properties, secondary structures,...
#2Paul R. Hansen(UCPH: University of Copenhagen)H-Index: 25
Last. Henrik Franzyk(UCPH: University of Copenhagen)H-Index: 29
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Previous optimisation studies of peptide/peptoid hybrids typically comprise comparison of structurally related analogues displaying different oligomer length and diverse side chains. The present work concerns a systematically constructed series of 16 closely related 12-mer oligomers with an alternating cationic/hydrophobic design, representing a wide range of hydrophobicity and differences in relative side-chain lengths. The aim was to explore and rationalise the structure–activity relationships...
Abstract The naturally occurring peptide indolicidin from bovine neutrophils exhibits strong biological activity against a broad spectrum of microorganisms. This is believed to arise from selective interactions with the negatively charged cytoplasmic lipid membrane found in bacteria. We have investigated the peptide interaction with supported lipid model membranes using a combination of complementary surface sensitive techniques: neutron reflectometry (NR), atomic force microscopy (AFM), and qua...
#2Ekta E. Kamble(Savitribai Phule Pune University)H-Index: 2
Last. Karishma Pardesi(Savitribai Phule Pune University)H-Index: 16
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The acronym ESKAPE includes six nosocomial pathogens that exhibit multidrug resistance and virulence: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. Persistent use of antibiotics has provoked the emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) bacteria, which render even the most effective drugs ineffective. Extended spectrum β-lactamase (ESBL) and carbapenemase producing Gram n...
Abstract Antimicrobial peptides (AMPs) are believed to be a promising class of antimicrobial agents against bacteria and fungi. To promote the clinical use of AMPs, their antimicrobial activity and susceptibility to protease degradation should be further improved. The antimicrobial peptide Jelleine-I was originally isolated from the royal jelly of honeybees (Apis mellifera) with a short sequence of PFKLSLHL-NH2 (953.24 Da). Here, a series of halogenated derivatives of the antimicrobial peptide J...
Using small angle X-ray and neutron scattering (SAXS/SANS) and detailed theoretical modelling we have elucidated the structure of the antimicrobial peptide, indolicidin, and the interaction with model lipid membranes of different anionic lipid compositions mimicking typical charge densities found in the cytoplasmic membrane of bacteria. First, we show that indolicidin displays a predominantly disordered, random chain conformation in solution with a small fraction (≈1%) of fiber-like nanostructur...
With a rapidly growing number of bacterial strains displaying resistance against conventional antibiotics, the development of novel types of antimicrobial agents represents an important health challenge. Antimicrobial peptides (AMPs) has attracted interest in this context, as these can be designed to display potent broad-spectrum antimicrobial as well as anti-inflammatory effects, but simultaneously low toxicity against human cells. Much of the work on AMPs has been focused on membrane interacti...
The present study describes the synthesis and biological studies of a small series of head-to-tail cyclic tetrapeptides of the general structure c(Lys‐β2,2‐Xaa‐Lys) containing one lipophilic β2,2-a ...
Last. Håvard Jenssen(RU: Roskilde University)H-Index: 40
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The work was funded by the Danish Council for Independent Research, Technology and Production, grant 4005‐00029; Strategic Project POCI‐01‐0145‐FEDER‐007440 funded by FEDER through Operational Programme Competitiveness Factors, the European Foundation for the Study of Diabetes (Novartis European Research Programme in Microvascular Complications of Diabetes), and FCT; and Pepper grant P30 AG028718 and NIGMS‐NIH P20GM109096 to EC.
Hydroxycoumarins and their based conjugates revealed a wide-ranged biological activity providing potential scaffolds to serve better in therapy. This work aims to synthesize six new azo-coumarinic conjugates termed SY1-SY6 and investigate their potentials as antitumor and antibacterial applicants. The synthesis of these conjugates started from cantabiline, which was employed as a synthetic precursor and comparable agent in the biological assessment. The antitumor activity of the conjugates was i...
In an attempt to find versatile and readily accessible coumarin scaffolds with a broad spectrum of biomedical properties, seven bisimidazole–coumarin conjugates were synthesized through several steps starting from metacetamol and malonic acid. Spectroscopical techniques including FTIR, 1H-NMR, and 13C-NMR were employed to confirm the chemical backbone of the synthesized conjugates. Their biomedical potentials to behave as anti-tumorous, anti-aerobic gram-negative bacterial, anti-anaerobic bacter...
Viral infections, such as those caused by Herpes Simplex Virus-1 (HSV-1) and SARS-CoV-2, affect millions of people each year. However, there are few antiviral drugs that can effectively treat these infections. The standard approach in the development of antiviral drugs involves the identification of a unique viral target, followed by the design of an agent that addresses that target. Antimicrobial peptides (AMPs) represent a novel source of potential antiviral drugs. AMPs have been shown to inac...
The Buchwald–Hartwig cross-coupling of 5-bromo-4-(furan-2-yl)pyrimidine with various anilines afforded the corresponding new 5-(arylamino)pyrimidines, the reaction being accelerated by microwave irradiation. Most of the obtained compounds proved to possess a high bacteriostatic in vitro effect against Mycobacterium tuberculosis H37Rv, Neisseria gonorrhoeae, and Staphylococcus aureus including Methicillin-resistant strain, which is stronger than that of the commercial drug Spectinomycin.
Peptoids, or poly-N-substituted glycines, are characterised by broad structural diversity. Compared to peptides, they are less restricted in rotation and lack backbone-derived H bonding. Nevertheless, certain side chains force the peptoid backbone into distinct conformations. Designable secondary structures like helices or nanosheets arise from this knowledge. Herein, we report the copper-catalysed alkyne-azide cycloaddition (CuAAC) of macrocycles to form innovative tube-like tricyclic peptoids,...
Supramolecular assembly and PEGylation (attachment of a polyethylene glycol polymer chain) of peptides can be an effective strategy to develop antimicrobial peptides with increased stability, antimicrobial efficacy and hemocompatibility. However, how the self-assembly properties and PEGylation affect their lipid membrane interaction is still an unanswered question. In this work, we use state-of-the-art small angle X-ray and neutron scattering (SAXS/SANS) together with neutron reflectometry (NR) ...