scholarly journals De Novo Designed Amphipathic α-Helical Antimicrobial Peptides Incorporating Dab and Dap Residues on the Polar Face To Treat the Gram-Negative Pathogen, Acinetobacter baumannii

2019 ◽  
Vol 62 (7) ◽  
pp. 3354-3366 ◽  
Author(s):  
Colin T. Mant ◽  
Ziqing Jiang ◽  
Lajos Gera ◽  
Tim Davis ◽  
Kirsten L. Nelson ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Acinetobacter Baumannii ◽  
De Novo ◽  
Gram Negative

scholarly journals Design of Novel Amphipathic α-Helical Antimicrobial Peptides with No Toxicity as Therapeutics against the Antibiotic-Resistant Gram-Negative Bacterial Pathogen, Acinetobacter Baumannii

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Mant CT ◽  
Jiang Z ◽  
Gera L ◽  
Davis T ◽  
Hodges RS
Keyword(s):  
Antimicrobial Activity ◽  
Antimicrobial Peptides ◽  
Acinetobacter Baumannii ◽  
De Novo ◽  
Bacterial Pathogen ◽  
Polymyxin B ◽  
Hemolysis Assay ◽  
Charged Residues ◽  
Positively Charged ◽  
Specificity Determinants

We designed de novo and synthesized two series of five 26-residue amphipathic α-helical cationic antimicrobial peptides (AMPs) with five or six positively charged residues (D-Lys, L-Dab (2,4-diaminobutyric acid) or L-Dap (2,3-diaminopropionic acid)) on the polar face where all other residues are in the D-conformation. Hemolytic activity against human red blood cells was determined using the most stringent conditions for the hemolysis assay, 18h at 37°C, 1% human erythrocytes and peptide concentrations up to 1000 μg/mL (~380 μM). Antimicrobial activity was determined against 7 Acinetobacter baumannii strains, resistant to polymyxin B and colistin (antibiotics of last resort) to show the effect of positively charged residues in two different locations on the polar face (positions 3, 7, 11, 18, 22 and 26 versus positions 3, 7, 14, 15, 22 and 26). All 10 peptides had two D-Lys residues in the center of the non-polar face as “specificity determinants” at positions 13 and 16 which provide specificity for prokaryotic cells over eukaryotic cells. Specificity determinants also maintain excellent antimicrobial activity in the presence of human sera. This study shows that the location and type of positively charged residue (Dab and Dap) on the polar face are critical to obtain the best therapeutic indices.

scholarly journals Deciphering Novel Antimicrobial Peptides from the Transcriptome of Papilio xuthus

Insects ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 776
Author(s):  
Joon Ha Lee ◽  
Hoyong Chung ◽  
Yong Pyo Shin ◽  
Mi-Ae Kim ◽  
Sathishkumar Natarajan ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
De Novo ◽  
Average Length ◽  
Transcriptome Assembly ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Swallowtail Butterfly ◽  
Papilio Xuthus ◽  
Antimicrobial Studies

An insect’s innate immune system is the front line of defense against many invading microorganisms. One of the important components of this defense system is antimicrobial peptides (AMPs). Papiliocin is a well-studied antimicrobial peptide (AMP) isolated from the swallowtail butterfly, Papilio xuthus, and it was previously reported to be effective against Gram-positive bacteria, Gram-negative bacteria, and fungi, particularly in drug resistant Gram-negative bacteria. Hence, we aimed to identify novel AMPs from Papilio xuthus using its transcriptome. We immunized the swallowtail butterfly with Escherichia coli, Staphylococcus aureus, Candida albicans, and the total RNA was isolated. De novo transcriptome assembly and functional annotations were conducted, and AMPs were predicted using an in-silico pipeline. The obtained 344,804,442 raw reads were then pre-processed to retrieve 312,509,806 (90.6%) total clean reads. A total of 38,272 unigenes were assembled with the average length of 1010 bp. Differential gene expression analysis identified 584 and 1409 upregulated and downregulated genes, respectively. The physicochemical, aggregation, and allergen propensity were used as filtration criteria. A total of 248 peptides were predicted using our in-house pipeline and the known AMPs were removed, resulting in 193 novel peptides. Finally, seven peptides were tested in vitro and three peptides (Px 5, 6, and 7) showed stronger antimicrobial activity against Gram-negative bacteria and yeast. All the tested peptides were non-allergens. The identified novel AMPs may serve as potential candidates for future antimicrobial studies.

scholarly journals Complete Genome Sequence of Acinetobacter baumannii Strain B8342, a Motility-Positive Clinical Isolate

2015 ◽  
Vol 3 (4) ◽  
Author(s):  
Saranya Vijaykumar ◽  
Veeraraghavan Balaji ◽  
Indranil Biswas
Keyword(s):  
Health Care ◽  
Acinetobacter Baumannii ◽  
Complete Genome Sequence ◽  
Complete Genome ◽  
De Novo ◽  
Clinical Strain ◽  
Sequencing Data ◽  
Gram Negative ◽  
Long Read ◽  
Health Care Associated Infections

Acinetobacter baumannii is an emerging Gram-negative pathogen responsible for health care–associated infections. In this study, we determined the genome of a motility-positive clinical strain, B8342, isolated from a hospital in southern India. The B8342 genome, which is 3.94 Mbp, was generated by de novo assembly of PacBio long-read sequencing data.

scholarly journals De Novo Design of Potent Antimicrobial Peptides

2004 ◽  
Vol 48 (9) ◽  
pp. 3349-3357 ◽  
Author(s):  
V. Frecer ◽  
B. Ho ◽  
J. L. Ding
Keyword(s):  
Antimicrobial Peptides ◽  
Rational Design ◽  
Lipid A ◽  
De Novo ◽  
Endotoxic Shock ◽  
Antimicrobial Properties ◽  
Antimicrobial Effect ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Qsar Analysis

ABSTRACT Lipopolysaccharide (LPS), shed by gram-negative bacteria during infection and antimicrobial therapy, may lead to lethal endotoxic shock syndrome. A rational design strategy based on the presumed mechanism of antibacterial effect was adopted to design cationic antimicrobial peptides capable of binding to LPS through tandemly repeated sequences of alternating cationic and nonpolar residues. The peptides were designed to achieve enhanced antimicrobial potency due to initial bacterial membrane binding with a reduced risk of endotoxic shock. The peptides designed displayed binding affinities to LPS and lipid A (LA) in the low micromolar range and by molecular modeling were predicted to form amphipathic β-hairpin-like structures when they bind to LPS or LA. They also exhibited strong effects against gram-negative bacteria, with MICs in the nanomolar range, and low cytotoxic and hemolytic activities at concentrations significantly exceeding their MICs. Quantitative structure-activity relationship (QSAR) analysis of peptide sequences and their antimicrobial, cytotoxic, and hemolytic activities revealed that site-directed substitutions of residues in the hydrophobic face of the amphipathic peptides with less lipophilic residues selectively decrease the hemolytic effect without significantly affecting the antimicrobial or cytotoxic activity. On the other hand, the antimicrobial effect can be enhanced by substitutions in the polar face with more polar residues, which increase the amphipathicity of the peptide. On the basis of the QSARs, new analogs that have strong antimicrobial effects but that lack hemolytic activity can be proposed. The findings highlight the importance of peptide amphipathicity and allow a rational method that can be used to dissociate the antimicrobial and hemolytic effects of cationic peptides, which have potent antimicrobial properties, to be proposed.

scholarly journals De Novo Design and In Vitro Testing of Antimicrobial Peptides against Gram-Negative Bacteria

2019 ◽  
Vol 12 (2) ◽  
pp. 82 ◽  
Author(s):  
Boris Vishnepolsky ◽  
George Zaalishvili ◽  
Margarita Karapetian ◽  
Tornike Nasrashvili ◽  
Nato Kuljanishvili ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Bacterial Resistance ◽  
De Novo ◽  
Antimicrobial Properties ◽  
Cell Penetrating Peptides ◽  
Short Peptides ◽  
Gram Negative Bacteria ◽  
Peptide Antibiotics ◽  
Gram Negative

Antimicrobial peptides (AMPs) have been identified as a potentially new class of antibiotics to combat bacterial resistance to conventional drugs. The design of de novo AMPs with high therapeutic indexes, low cost of synthesis, high resistance to proteases and high bioavailability remains a challenge. Such design requires computational modeling of antimicrobial properties. Currently, most computational methods cannot accurately calculate antimicrobial potency against particular strains of bacterial pathogens. We developed a tool for AMP prediction (Special Prediction (SP) tool) and made it available on our Web site (https://dbaasp.org/prediction). Based on this tool, a simple algorithm for the design of de novo AMPs (DSP) was created. We used DSP to design short peptides with high therapeutic indexes against gram-negative bacteria. The predicted peptides have been synthesized and tested in vitro against a panel of gram-negative bacteria, including drug resistant ones. Predicted activity against Escherichia coli ATCC 25922 was experimentally confirmed for 14 out of 15 peptides. Further improvements for designed peptides included the synthesis of D-enantiomers, which are traditionally used to increase resistance against proteases. One synthetic D-peptide (SP15D) possesses one of the lowest values of minimum inhibitory concentration (MIC) among all DBAASP database short peptides at the time of the submission of this article, while being highly stable against proteases and having a high therapeutic index. The mode of anti-bacterial action, assessed by fluorescence microscopy, shows that SP15D acts similarly to cell penetrating peptides. SP15D can be considered a promising candidate for the development of peptide antibiotics. We plan further exploratory studies with the SP tool, aiming at finding peptides which are active against other pathogenic organisms.

scholarly journals Proteomic response of Escherichia coli to a membrane lytic and iron chelating truncated Amaranthus tricolor defensin

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Tessa B. Moyer ◽  
Ashleigh L. Purvis ◽  
Andrew J. Wommack ◽  
Leslie M. Hicks
Keyword(s):  
Escherichia Coli ◽  
Antibacterial Activity ◽  
Antimicrobial Peptides ◽  
Mechanism Of Action ◽  
Gram Negative Bacteria ◽  
Amaranthus Tricolor ◽  
Core Motif ◽  
Gram Negative ◽  
E Coli ◽  
Membrane Lysis

Abstract Background Plant defensins are a broadly distributed family of antimicrobial peptides which have been primarily studied for agriculturally relevant antifungal activity. Recent studies have probed defensins against Gram-negative bacteria revealing evidence for multiple mechanisms of action including membrane lysis and ribosomal inhibition. Herein, a truncated synthetic analog containing the γ-core motif of Amaranthus tricolor DEF2 (Atr-DEF2) reveals Gram-negative antibacterial activity and its mechanism of action is probed via proteomics, outer membrane permeability studies, and iron reduction/chelation assays. Results Atr-DEF2(G39-C54) demonstrated activity against two Gram-negative human bacterial pathogens, Escherichia coli and Klebsiella pneumoniae. Quantitative proteomics revealed changes in the E. coli proteome in response to treatment of sub-lethal concentrations of the truncated defensin, including bacterial outer membrane (OM) and iron acquisition/processing related proteins. Modification of OM charge is a common response of Gram-negative bacteria to membrane lytic antimicrobial peptides (AMPs) to reduce electrostatic interactions, and this mechanism of action was confirmed for Atr-DEF2(G39-C54) via an N-phenylnaphthalen-1-amine uptake assay. Additionally, in vitro assays confirmed the capacity of Atr-DEF2(G39-C54) to reduce Fe3+ and chelate Fe2+ at cell culture relevant concentrations, thus limiting the availability of essential enzymatic cofactors. Conclusions This study highlights the utility of plant defensin γ-core motif synthetic analogs for characterization of novel defensin activity. Proteomic changes in E. coli after treatment with Atr-DEF2(G39-C54) supported the hypothesis that membrane lysis is an important component of γ-core motif mediated antibacterial activity but also emphasized that other properties, such as metal sequestration, may contribute to a multifaceted mechanism of action.

scholarly journals Antimicrobial-impregnated and -coated shunt catheters for prevention of infections in patients with hydrocephalus: a systematic review and meta-analysis

2015 ◽  
Vol 122 (5) ◽  
pp. 1096-1112 ◽  
Author(s):  
Athanasios A. Konstantelias ◽  
Konstantinos Z. Vardakas ◽  
Konstantinos A. Polyzos ◽  
Giannoula S. Tansarli ◽  
Matthew E. Falagas
Keyword(s):  
De Novo ◽  
Meta Analysis ◽  
Ventricular Drainage ◽  
Gram Negative ◽  
Ventriculoperitoneal Shunting ◽  
Csf Shunting ◽  
Statistical Heterogeneity ◽  
Catheter Implantation ◽  
Prevention Of Infections ◽  
Definition Of

OBJECT The aim of this study was to evaluate the effectiveness of antimicrobial-impregnated and -coated shunt catheters (antimicrobial catheters) in reducing the risk of infection in patients undergoing CSF shunting or ventricular drainage. METHODS The PubMed and Scopus databases were searched. Catheter implantation was classified as either shunting (mainly ventriculoperitoneal shunting) or ventricular drainage (mainly external [EVD]). Studies evaluating antibioticimpregnated catheters (AICs), silver-coated catheters (SCCs), and hydrogel-coated catheters (HCCs) were included. A random effects model meta-analysis was performed. RESULTS Thirty-six studies (7 randomized and 29 nonrandomized, 16,796 procedures) were included. The majority of data derive from studies on the effectiveness of AICs, followed by studies on the effectiveness of SCCs. Statistical heterogeneity was observed in several analyses. Antimicrobial shunt catheters (AICs, SCCs) were associated with lower risk for CSF catheter–associated infections than conventional catheters (CCs) (RR 0.44, 95% CI 0.35–0.56). Fewer infections developed in the patients treated with antimicrobial catheters regardless of randomization, number of participating centers, funding, shunting or ventricular drainage, definition of infections, de novo implantation, and rate of infections in the study. There was no difference regarding gram-positive bacteria, all staphylococci, coagulase-negative streptococci, and Staphylococcus aureus, when analyzed separately. On the contrary, the risk for methicillin-resistant S. aureus (MRSA, RR 2.64, 95% CI 1.26–5.51), nonstaphylococcal (RR 1.75, 95% CI 1.22–2.52), and gram-negative bacterial (RR 2.13, 95% CI 1.33–3.43) infections increased with antimicrobial shunt catheters. CONCLUSIONS Based on data mainly from nonrandomized studies, AICs and SCCs reduce the risk for infection in patients undergoing CSF shunting. Future studies should evaluate the higher risk for MRSA and gram-negative infections. Additional trials are needed to investigate the comparative effectiveness of the different types of antimicrobial catheters.

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