scholarly journals Comparison of a Short Linear Antimicrobial Peptide with Its Disulfide-Cyclized and Cyclotide-Grafted Variants against Clinically Relevant Pathogens

2021 ◽  
Vol 9 (6) ◽  
pp. 1249
Author(s):  
Johannes Koehbach ◽  
Jurnorain Gani ◽  
Kai Hilpert ◽  
David J Craik
Keyword(s):  
Antimicrobial Activity ◽  
Antimicrobial Peptide ◽  
Human Serum ◽  
World Health ◽  
Resistant Bacteria ◽  
Moderate Activity ◽  
Antimicrobial Compounds ◽  
Strong Activity ◽  
Linear Peptide ◽  
Linear Version

According to the World Health Organization (WHO) the development of resistance against antibiotics by microbes is one of the most pressing health concerns. The situation will intensify since only a few pharmacological companies are currently developing novel antimicrobial compounds. Discovery and development of novel antimicrobial compounds with new modes of action are urgently needed. Antimicrobial peptides (AMPs) are known to be able to kill multidrug-resistant bacteria and, therefore, of interest to be developed into antimicrobial drugs. Proteolytic stability and toxicities of these peptides are challenges to overcome, and one strategy frequently used to address stability is cyclization. Here we introduced a disulfide-bond to cyclize a potent and nontoxic 9mer peptide and, in addition, as a proof-of-concept study, grafted this peptide into loop 6 of the cyclotide MCoTI-II. This is the first time an antimicrobial peptide has been successfully grafted onto the cyclotide scaffold. The disulfide-cyclized and grafted cyclotide showed moderate activity in broth and strong activity in 1/5 broth against clinically relevant resistant pathogens. The linear peptide showed superior activity in both conditions. The half-life time in 100% human serum was determined, for the linear peptide, to be 13 min, for the simple disulfide-cyclized peptide, 9 min, and, for the grafted cyclotide 7 h 15 min. The addition of 10% human serum led to a loss of antimicrobial activity for the different organisms, ranging from 1 to >8-fold for the cyclotide. For the disulfide-cyclized version and the linear version, activity also dropped to different degrees, 2 to 18-fold, and 1 to 30-fold respectively. Despite the massive difference in stability, the linear peptide still showed superior antimicrobial activity. The cyclotide and the disulfide-cyclized version demonstrated a slower bactericidal effect than the linear version. All three peptides were stable at high and low pH, and had very low hemolytic and cytotoxic activity.

scholarly journals Antimicrobial Activity and HPLC Fingerprinting of CrudeOcimumExtracts

2011 ◽  
Vol 8 (3) ◽  
pp. 1430-1437 ◽  
Author(s):  
S. S. Deo ◽  
F. Inam ◽  
R. P. Mahashabde
Keyword(s):  
Antimicrobial Activity ◽  
Methanolic Extract ◽  
Ocimum Sanctum ◽  
Moderate Activity ◽  
Aqueous Extracts ◽  
Gram Positive ◽  
Strong Activity ◽  
Gram Negative ◽  
E Coli ◽  
Strong Antimicrobial Activity

The antimicrobial activity of crude methanolic and aqueous extracts ofOcimum sanctumandOcimum kilimandsacharicumagainst gram positive, gram negative and antifungal activity was evaluated to find the zone of inhibition and to set a HPLC profile or fingerprint of these extracts. The crude methanolic extract ofOcimum sanctumshowed strong antimicrobial activity againstS.aureusandC. albicansand moderate activity againstE. coliandB. subtilis. The crude methanolic extract ofOcimum kilimandsacharicumshowed strong antimicrobial activity againstS. aureus, E. coliandC. albicansat higher concentration, same as that shown by the standard forC. albicans. It showed moderate activity againstB. subtilis. The crude aqueous extracts of Ocimum sanctum showed strong antimicrobial activity againstS.aureusand moderate against others. Whereas the crude aqueous extracts ofOcimum kilimandsacharicumshowed moderate activity against the gram positive and gram negative organisms and strong activity againstC. albicansat higher concentration, same as that shown by the standard forC. albicans.

scholarly journals Biological Activities of Synthetic Analogs of Halocidin, an Antimicrobial Peptide from the Tunicate Halocynthia aurantium

2003 ◽  
Vol 47 (8) ◽  
pp. 2481-2486 ◽  
Author(s):  
Woong Sik Jang ◽  
Chong Han Kim ◽  
Kyu Nam Kim ◽  
Shin Yong Park ◽  
Joon Ha Lee ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Biological Activities ◽  
Antimicrobial Activities ◽  
Resistant Bacteria ◽  
Amino Terminus ◽  
Antibiotic Resistant ◽  
Strong Activity ◽  
C Terminus ◽  
Lysine Residues ◽  
Carboxyl Terminal

ABSTRACT Halocidin is a heterodimer antimicrobial peptide previously isolated from the tunicate Halocynthia aurantium. Based on the larger monomer (18Hc) of halocidin, nine halocidin congeners, including a series of 6 peptides truncated successively from the carboxyl-terminal end of 18Hc and 3 analogs (18HcKK, K19Hc, and K19HcKK), which have lysine residues in place of two internal histidines or have a lysine added to the amino terminus of the 18Hc molecule, were prepared. Each peptide was also converted into a homodimeric version. The antimicrobial activities of halocidin congeners truncated from the C terminus were dramatically decreased, suggesting that the full length of 18Hc is required for maintaining its maximum antimicrobial activity. Dimer forms of halocidin congeners exhibited stronger antimicrobial activities than the monomer of the corresponding peptide. Four dimer peptides (di-18Hc, di-18HcKK, di-K19Hc, and di-K19HcKK) were analyzed for antimicrobial activities against 10 clinically isolated antibiotic-resistant bacteria in elevated concentrations of NaCl or MgCl2. Of the peptides studied here, di-K19Hc retained invariably strong activity against all bacteria in diverse conditions and also showed much reduced hemolytic activity against human erythrocytes.

scholarly journals All d-Lysine Analogues of the Antimicrobial Peptide HPA3NT3-A2 Increased Serum Stability and without Drug Resistance

2020 ◽  
Vol 21 (16) ◽  
pp. 5632
Author(s):  
Jong-Kook Lee ◽  
Yoonkyung Park
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Activity ◽  
Antimicrobial Peptide ◽  
Proteolytic Enzymes ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Peptide Bonds ◽  
Drug Resistant Bacteria ◽  
Antibiotic Drugs ◽  
Strong Antimicrobial Activity

Novel antibiotic drugs are urgently needed because of the increase in drug-resistant bacteria. The use of antimicrobial peptides has been suggested to replace antibiotics as they have strong antimicrobial activity and can be extracted from living organisms such as insects, marine organisms, and mammals. HPA3NT3-A2 ([Ala1,8] HPA3NT3) is an antimicrobial peptide that is an analogue of the HP (2–20) peptide derived from Helicobacter pylori ribosomal protein L1. Although this peptide was shown to have strong antimicrobial activity against drug-resistant bacteria, it also showed lower toxicity against sheep red blood cells (RBCs) and HaCaT cells compared to HPA3NT3. The l-Lys residues of HPA3NT3-A2 was substituted with d-Lys residues (HPA3NT3-A2D; [d-Lys2,5,6,9,10,15] HPA3NT3-A2) to prevent the cleavage of peptide bonds by proteolytic enzymes under physiological conditions. This peptide showed an increased half-life and maintained its antimicrobial activity in the serum against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) (pathogen). Furthermore, the antimicrobial activity of HPA3NT3-A2D was not significantly affected in the presence of mono- or divalent ions (Na+, Mg2+, Ca2+). Finally, l- or d-HPA3NT3-A2 peptides exhibited the strongest antimicrobial activity against antibiotic-resistant bacteria and failed to induce resistance in Staphylococcus aureus after 12 passages.

scholarly journals Antimicrobial Compounds from the Shoots of Arctotis Arctotoides

1970 ◽  
Vol 43 (1) ◽  
pp. 89-96 ◽  
Author(s):  
Nasim Sultana ◽  
AJ Afolayan ◽  
Rauf Ahmed Bhuiyan
Keyword(s):  
Antimicrobial Activity ◽  
Bacterial Species ◽  
Perennial Herb ◽  
Moderate Activity ◽  
Gram Negative Bacteria ◽  
Antimicrobial Compounds ◽  
Eastern Cape ◽  
Literature Study ◽  
Bioassay Guided Fractionation ◽  
Comparative Literature Study

Arctotis arctotoides is a perennial herb used medicinally for the treatment of various ailments in the Eastern Cape, South Africa. Different extracts from the shoots of this herb showed antimicrobial activity against some bacterial species. Bioassay guided fractionation of the extracts has led to the isolation of three compounds, glycerol-1- docosanoate, zaluzanin C and perydiscolic acid. The structures were elucidated on the basis of their one- and two-dimensional NMR spectral analysis and by a comparative literature study. The evaluation of antimicrobial activity of the compounds revealed moderate activity against four Gram-positive and two Gram-negative bacteria. Keywords: Arctotis arctotoides, Asteraceae, Antibacterial activity, Glycerol-1- docosanoate, Zaluzanin C, Perydiscolic acid. DOI: 10.3329.bjsir.v43i1.860 Bangladesh J. Sci. Ind. Res. 43(1), 89-96, 2008

scholarly journals Transcriptome Analysis of Psacothea hilaris: De Novo Assembly and Antimicrobial Peptide Prediction

Insects ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 676 ◽  
Author(s):  
Joon Ha Lee ◽  
Hoyong Chung ◽  
Yong Pyo Shin ◽  
In-Woo Kim ◽  
Sathishkumar Natarajan ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Antifungal Activity ◽  
Antimicrobial Peptide ◽  
De Novo ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Bacterial Strains ◽  
Illumina Platform ◽  
E Coli ◽  
Innate Defense

Antimicrobial peptides (AMPs) are the frontline innate defense system evolutionarily preserved in insects to combat invading pathogens. These AMPs could serve as an alternative to classical antibiotics to overcome the burden of treating multidrug resistant bacteria. Psacotheasin, a knottin type AMP was isolated from Psacothea hilaris and shown to exhibit antimicrobial activity, especially against fungi through apoptosis mediated cell death. In this study, we aimed to identify novel probable AMPs from Psacothea hilaris, the yellow spotted longicorn beetle. The beetle was immunized with the two bacterial strains (E. coli and S. aureus), and the yeast strain C. albicans. After immunization, total RNA was isolated and sequenced in Illumina platform. Then, beetle transcriptome was de novo assembled and searched for putative AMPs with the known physiochemical features of the AMPs. A selection of AMP candidates were synthesized and tested for antimicrobial activity. Four peptides showed stronger activity against E. coli than the control AMP, melittin while one peptide showed similar activity against S. aureus. Moreover, four peptides and two peptides showed antifungal activity stronger than and similar to melittin, respectively. Collectively one peptide showed both antibacterial and antifungal activity superior to melittin; thus, it provides a potent antimicrobial peptide. All the peptides showed no hemolysis in all the tested concentrations. These results suggest that in silico mining of insects’ transcriptome could be a promising tool to obtain and optimize novel AMPs for human needs.

scholarly journals Replacement of l-Amino Acids by d-Amino Acids in the Antimicrobial Peptide Ranalexin and Its Consequences for Antimicrobial Activity and Biodistribution

Molecules ◽  
2019 ◽  
Vol 24 (16) ◽  
pp. 2987 ◽  
Author(s):  
Cornelius Domhan ◽  
Philipp Uhl ◽  
Christian Kleist ◽  
Stefan Zimmermann ◽  
Florian Umstätter ◽  
...  
Keyword(s):  
Amino Acids ◽  
Antimicrobial Activity ◽  
Antimicrobial Peptide ◽  
The Body ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Strong Antimicrobial Activity

Infections caused by multidrug-resistant bacteria are a global emerging problem. New antibiotics that rely on innovative modes of action are urgently needed. Ranalexin is a potent antimicrobial peptide (AMP) produced in the skin of the American bullfrog Rana catesbeiana. Despite strong antimicrobial activity against Gram-positive bacteria, ranalexin shows disadvantages such as poor pharmacokinetics. To tackle these problems, a ranalexin derivative consisting exclusively of d-amino acids (named danalexin) was synthesized and compared to the original ranalexin for its antimicrobial potential and its biodistribution properties in a rat model. Danalexin showed improved biodistribution with an extended retention in the organisms of Wistar rats when compared to ranalexin. While ranalexin is rapidly cleared from the body, danalexin is retained primarily in the kidneys. Remarkably, both peptides showed strong antimicrobial activity against Gram-positive bacteria and Gram-negative bacteria of the genus Acinetobacter with minimum inhibitory concentrations (MICs) between 4 and 16 mg/L (1.9–7.6 µM). Moreover, both peptides showed lower antimicrobial activities with MICs ≥32 mg/L (≥15.2 µM) against further Gram-negative bacteria. The preservation of antimicrobial activity proves that the configuration of the amino acids does not affect the anticipated mechanism of action, namely pore formation.

scholarly journals Activity of the De Novo Engineered Antimicrobial Peptide WLBU2 against Pseudomonas aeruginosa in Human Serum and Whole Blood: Implications for Systemic Applications

2005 ◽  
Vol 49 (8) ◽  
pp. 3208-3216 ◽  
Author(s):  
Berthony Deslouches ◽  
Kazi Islam ◽  
Jodi K. Craigo ◽  
Shruti M. Paranjape ◽  
Ronald C. Montelaro ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Peptide ◽  
Human Serum ◽  
Whole Blood ◽  
De Novo ◽  
Host Cells ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Bacterial Killing ◽  
Biologically Relevant

ABSTRACT Cationic amphipathic peptides have been extensively investigated as a potential source of new antimicrobials that can complement current antibiotic regimens in the face of emerging drug-resistant bacteria. However, the suppression of antimicrobial activity under certain biologically relevant conditions (e.g., serum and physiological salt concentrations) has hampered efforts to develop safe and effective antimicrobial peptides for clinical use. We have analyzed the activity and selectivity of the human peptide LL37 and the de novo engineered antimicrobial peptide WLBU2 in several biologically relevant conditions. The host-derived synthetic peptide LL37 displayed high activity against Pseudomonas aeruginosa but demonstrated staphylococcus-specific sensitivity to NaCl concentrations varying from 50 to 300 mM. Moreover, LL37 potency was variably suppressed in the presence of 1 to 6 mM Mg2+ and Ca2+ ions. In contrast, WLBU2 maintained its activity in NaCl and physiologic serum concentrations of Mg2+ and Ca2+. WLBU2 is able to kill P. aeruginosa (106 CFU/ml) in human serum, with a minimum bactericidal concentration of <9 μM. Conversely, LL37 is inactive in the presence of human serum. Bacterial killing kinetic assays in serum revealed that WLBU2 achieved complete bacterial killing in 20 min. Consistent with these results was the ability of WLBU2 (15 to 20 μM) to eradicate bacteria from ex vivo samples of whole blood. The selectivity of WLBU2 was further demonstrated by its ability to specifically eliminate P. aeruginosa in coculture with human monocytes or skin fibroblasts without detectable adverse effects to the host cells. Finally, WLBU2 displayed potent efficacy against P. aeruginosa in an intraperitoneal infection model using female Swiss Webster mice. These results establish a potential application of WLBU2 in the treatment of bacterial sepsis.

scholarly journals Discovery of antimicrobial compounds from Lendenfeldia, Ircinia and Dysidea sponges using bioassay guided fractionation of marine extracts

2018 ◽  
Author(s):  
Mojdeh Dinarvand ◽  
Nicholas Proschogo ◽  
Malcolm P. Spain ◽  
Gayathri Nagalingam ◽  
James A. Triccas ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Small Molecules ◽  
Therapeutic Index ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Antimicrobial Compounds ◽  
Multidrug Resistant Bacteria ◽  
Synthetic Compounds ◽  
The World ◽  
Bioassay Guided Fractionation

ABSTRACTMultidrug resistant bacteria have emerged as a threat to public health all over the world. At the same time, the discovery of new bioactive small molecules with antimicrobial activity and suitable pharmacological properties has waned. Herein we report the screening of marine extracts to identify novel compounds with antimicrobial activity. Bioassay guided fractionation has enabled the discovery and identification of a family of simple amines with promising activity against methicillin resistant Staphylococcus aureus (MRSA). To confirm the natural product structures proposed, these compounds and analogues have been prepared synthetically. Several of the synthetic analogues showed promising bioactivity against the medically important pathogens MRSA (MICs to 12.5 µM), Mycobacterium tuberculosis (MICs to 0.02 µM), uropathogenic Escherichia coli (MIC 6.2 µM) and Pseudomonas aeruginosa (MIC 3.1 µM). Cross-referencing antimicrobial activity and toxicity show that these synthetic compounds display a favourable therapeutic index for their target pathogens.

scholarly journals Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)

Antibiotics ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 844
Author(s):  
Philip Storck ◽  
Florian Umstätter ◽  
Sabrina Wohlfart ◽  
Cornelius Domhan ◽  
Christian Kleist ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Antimicrobial Activity ◽  
Fatty Acid ◽  
Antimicrobial Peptide ◽  
Saturated Fatty Acids ◽  
Resistant Bacteria ◽  
Bacterial Strains ◽  
High Antimicrobial Activity ◽  
Hydrophobic Motif

The increasing number of infections caused by multidrug-resistant bacteria requires an intensified search for new antibiotics. Pep19-4LF is a synthetic antimicrobial peptide (GKKYRRFRWKFKGKLFLFG) that was previously designed with the main focus on high antimicrobial activity. The hydrophobic motif, LFLFG, was found to be essential for antimicrobial activity. However, this motif shows several limitations such as aggregation in biological media, low solubility, and small yields in peptide synthesis. In order to obtain more appropriate peptide characteristics, the hydrophobic motif was replaced with fatty acids. For this purpose, a shortened variant of Pep19-4LF (Pep19-short; GKKYRRFRWKFKGK) was synthesized and covalently linked to saturated fatty acids of different chain lengths. The peptide conjugates were tested with respect to their antibacterial activity by microdilution experiments on different bacterial strains. The length of the fatty acid was found to be directly correlated to the antimicrobial activity up to an ideal chain length (undecanoic acid, C11:0). This conjugate showed high antimicrobial activity in absence of toxicity. Time–kill studies revealed a fast and bactericidal mode of action. Furthermore, the first in vivo experiments of the conjugate in rodents demonstrated pharmacokinetics appropriate for application as a drug. These results clearly indicate that the hydrophobic motif of the peptide can be replaced by a single fatty acid of medium length, simplifying the design of this antimicrobial peptide while retaining high antimicrobial activity in the absence of toxicity.

scholarly journals Activity of the Lichen Usnea steineri and its Major Metabolites against Gram–positive, Multidrug–resistant Bacteria

2016 ◽  
Vol 11 (4) ◽  
pp. 1934578X1601100 ◽  
Author(s):  
Marcos G. Tozatti ◽  
Daniele S. Ferreira ◽  
Lúzio G. Bocalon Flauzino ◽  
Thaís da Silva Moraes ◽  
Carlos H. G. Martins ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Synergistic Effects ◽  
Bacterial Species ◽  
Usnic Acid ◽  
Acetone Extract ◽  
Resistant Bacteria ◽  
Strong Activity ◽  
Phytochemical Study ◽  
Isolation And Characterization

The antimicrobial activity and possible synergistic effects of extracts and compounds isolated from Usnea steineri were evaluated against four resistant bacterial species. A phytochemical study of the acetone extract of U. steineri resulted in the isolation and characterization of difractaic acid and (+)–usnic acid as the main compounds. The acetone extract showed strong activity (less than 10 μg/mL) against resistant strains of Staphylococcus epidermidis and Enterococcus faecalis, and (+)–usnic acid exhibited strong activity against S. epidermidis (MIC 3.12 μg/mL), S. aureus and S. haemolyticus (MIC 12.5 μg/mL). Combinations of penicillin and tetracycline with (+)–usnic acid did not show any synergistic antimicrobial effects. Difractaic acid was inactive. Our results showed that the acetone extract of U. steineri possesses significant in vitro antimicrobial activity, which is likely related to the presence of (+)–usnic acid.

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