Synthesis and antibacterial activity of trivalent ultrashort Arg-Trp-based antimicrobial peptides (AMPs)

Hoffknecht, Barbara C.; Albada, Bauke; Sturm, Marina; Prochnow, Pascal; Bandow, Julia E.; Metzler‐Nolte, Nils

doi:10.1039/c4md00327f

Cited by 10 publications

(9 citation statements)

References 29 publications

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“…This leads to the conclusion that the presence of ac ertain number of Arg and Trpr esidues is more important than their chemicall inkage.I n line with previousf indings, [18] peptides with more than nine residues do not show increased activity,b ut insteadl ower activity. Fifteen different compounds, from mono-tot rivalent, were synthesized in highpurity and acceptable yields, using three different scaffolds.…”

Section: Discussionsupporting

confidence: 90%

“…Interestingly,t he trivalent compound 3c is fairly active, and is only aboutt wo-to fivefold weaker than compound 7a,w hich containst he same number of Arg and Trpr esidues, but has as lightly higher molecular weight; 1332 Da for 7a vs. 1782 Da for 3c). This leads to the conclusion that the presence of ac ertain number of Arg and Trpr esidues is more important than their chemicall inkage.I n line with previousf indings, [18] peptides with more than nine residues do not show increased activity,b ut insteadl ower activity. We could showt hat by multivalent display,o therwise inactive ultrashort peptides (only 2-3 AA long) can become very active against bacteria.…”

Section: Discussionsupporting

confidence: 90%

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Influence of the Multivalency of Ultrashort Arg‐Trp‐Based Antimicrobial Peptides (AMP) on Their Antibacterial Activity

et al. 2015

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Peptide dendrimers are a class of molecules of high interest in the search for new antibiotics. We used microwave-assisted, copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC; "click" chemistry) for the simple and versatile synthesis of a new class of multivalent antimicrobial peptides (AMPs) containing solely arginine and tryptophan residues. To investigate the influence of multivalency on antibacterial activity, short solid-phase- synthesized azide-modified Arg-Trp-containing peptides were "clicked" to three different alkyne-modified benzene scaffolds to access scaffolds with one, two, or three peptides. The antibacterial activity of 15 new AMPs was investigated by minimal inhibitory concentration (MIC) assays on five different bacterial strains, including a multidrug-resistant Staphylococcus aureus (MRSA) strain. With ultrashort (2-3 residues) peptides, a clear synergistic effect of the trivalent display was observed, whereas this effect was not apparent with longer peptides. The best candidates showed activities in the low-micromolar range against Gram-positive MRSA. Surprisingly, the best activity against Gram-negative Acinetobacter baumannii was observed with an ultrashort dipeptide on the trivalent scaffold (MIC: 7.5 μM). The hemolytic activity was explored for the three most active peptides. At concentrations ten times the MIC values, <1 % hemolysis of red blood cells was observed.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 90%

Influence of the Multivalency of Ultrashort Arg‐Trp‐Based Antimicrobial Peptides (AMP) on Their Antibacterial Activity

et al. 2015

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“…26 Conjugation of the ultrashort synAMP alkynes to the azido scaffolds was performed using (EtO) 3 PCuI in the presence of base under microwave-assisted heating; isolated yields of 25−36% were obtained. 27 Even though we observed preorganization in the Xray crystal structure of the hexasubstituted benzene scaffold, we were a bit skeptical as to the effect on the antibacterial activity that would be observed, since significantly larger groups were now attached. Much to our delight, a trivalent construct with the RWR tripeptide attached to the flexible scaffold was 6−12 times less active against MRSA than the preorganized system (structure 19, Chart 5; the MIC values were 12−24 vs 2 μM, respectively).…”

Section: Organometallic Antimicrobial Peptidesmentioning

confidence: 87%

“…Although this was initially done in the solution phase, we also developed new linker molecules that provided alkyne-functionalized peptides after standard SPPS . Conjugation of the ultrashort synAMP alkynes to the azido scaffolds was performed using (EtO) 3 PCuI in the presence of base under microwave-assisted heating; isolated yields of 25–36% were obtained . Even though we observed preorganization in the X-ray crystal structure of the hexasubstituted benzene scaffold, we were a bit skeptical as to the effect on the antibacterial activity that would be observed, since significantly larger groups were now attached.…”

Section: Unraveling the Mode Of Action Of Small Cationic Ampsmentioning

confidence: 99%

Highly Potent Antibacterial Organometallic Peptide Conjugates

2017

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Resistance of pathogenic bacteria against currently marketed antibiotics is again increasing. To meet the societal need for effective cures, scientists are faced with the challenge of developing more potent but equally bacteria-specific drugs. Currently, most efforts are directed toward the modification of existing antibiotics, but ideally, compounds with a new mode of action are required. In this Account, we detail our findings in the area of novel metal-based antibiotics. Our strategy is based on the modification of simple antimicrobial peptides (AMPs) with organometallic agents, resulting in organometallic AMPs (OM-AMPs). Since bacteria have most likely never encountered these synthetically prepared unnatural organometallic agents, we anticipated that such agents could well become potentiating players in the antibiotics arena. Moreover, exploiting some of the particular properties of metal complexes should also help to elucidate the mode of action of small cationic AMPs, the molecular details of which have remained elusive despite intensive efforts. Using standard Fmoc/tBu-based solid-phase peptide synthesis approaches, we have prepared various organometallic-peptide conjugates with covalently linked group 8 and 9 metallocenes (ferrocene, ruthenocene, osmocene, and cobaltocenium). As a starting point we took the (RW) antibacterial hexapeptide lead structure. After modifying the peptide sequence (generations 1 and 2), changing the nature and position of the organometallic group (generation 3), and optimizing the amino acid chirality (generation 5), we identified several organometallic antibacterial peptides that are currently among the most active synthetic AMPs (synAMPs) that have ever been prepared. Through these rational and systematic optimizations, we were able to increase the antibacterial activity of a short non-organometallic synAMP 18-fold to submicromolar activity, rivaling the activity of vancomycin (often the drug of last resort) against methicillin-resistant Staphylococcus aureus (MRSA). Moreover, by making use of the unique physicochemical properties of ruthenocene, we were able to determine the mode of action of these short AMPs in unprecedented detail. We propose that the OM-AMP integrates into the bacterial membrane and changes its biophysical properties, which ultimately results in detachment of vital enzymes for respiration and cell-wall biosynthesis such as specifically cytochrome c and MurG from their locations in the membrane. Further explorations of these small OM-AMP derivatives that are summarized in this Account include lipid substitution, multivalent display of metalated di- or tripeptides on a trivalent scaffold with different linkers, and increasing the metal-to-peptide ratio such that every tryptophan in the (RW) scaffold is eventually replaced by a metalated lysine. While initial experiments with our OM-AMPs for systemic applications were largely disappointing, these OM-AMPs turned out to be potent antibiotics for topical applications. In this sense, two applications are described...

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“…The AMPs were more active against the grampositive compared to the gram-negative bacteria. Comparison of the activity with the Linear (RW) 3 -NH 2 suggests that the presence of certain number of amino acids in the close vicinity is more important than their relative spatial orientation (Hoffknecht et al, 2015). High antimicrobial property was obtained by increasing the hydrophobic volume of the side chains of the amino acid residues.…”

Section: Synthetic Cyclic Peptidesmentioning

confidence: 98%

Antimicrobial Peptides and Proteins: From Nature’s Reservoir to the Laboratory and Beyond

2021

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Rapid rise of antimicrobial resistance against conventional antimicrobials, resurgence of multidrug resistant microbes and the slowdown in the development of new classes of antimicrobials, necessitates the urgent development of alternate classes of therapeutic molecules. Antimicrobial peptides (AMPs) are small proteins present in different lifeforms in nature that provide defense against microbial infections. They have been effective components of the host defense system for a very long time. The fact that the development of resistance by the microbes against the AMPs is relatively slower or delayed compared to that against the conventional antibiotics, makes them prospective alternative therapeutics of the future. Several thousands of AMPs have been isolated from various natural sources like microorganisms, plants, insects, crustaceans, animals, humans, etc. to date. However, only a few of them have been translated commercially to the market so far. This is because of some inherent drawbacks of the naturally obtained AMPs like 1) short half-life owing to the susceptibility to protease degradation, 2) inactivity at physiological salt concentrations, 3) cytotoxicity to host cells, 4) lack of appropriate strategies for sustained and targeted delivery of the AMPs. This has led to a surge of interest in the development of synthetic AMPs which would retain or improve the antimicrobial potency along with circumventing the disadvantages of the natural analogs. The development of synthetic AMPs is inspired by natural designs and sequences and strengthened by the fusion with various synthetic elements. Generation of the synthetic designs are based on various strategies like sequence truncation, mutation, cyclization and introduction of unnatural amino acids and synthons. In this review, we have described some of the AMPs isolated from the vast repertoire of natural sources, and subsequently described the various synthetic designs that have been developed based on the templates of natural AMPs or from de novo design to make commercially viable therapeutics of the future. This review entails the journey of the AMPs from their natural sources to the laboratory.

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Synthesis and antibacterial activity of trivalent ultrashort Arg-Trp-based antimicrobial peptides (AMPs)

Cited by 10 publications

References 29 publications

Influence of the Multivalency of Ultrashort Arg‐Trp‐Based Antimicrobial Peptides (AMP) on Their Antibacterial Activity

Influence of the Multivalency of Ultrashort Arg‐Trp‐Based Antimicrobial Peptides (AMP) on Their Antibacterial Activity

Highly Potent Antibacterial Organometallic Peptide Conjugates

Antimicrobial Peptides and Proteins: From Nature’s Reservoir to the Laboratory and Beyond

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