In Vitro Activity and Potency of an Intravenously Injected Antimicrobial Peptide and Its
            <scp>dl</scp>
            Amino Acid Analog in Mice Infected with Bacteria

Braunstein, Amir; Papo, Niv; Shai, Yechiel

doi:10.1128/aac.48.8.3127-3129.2004

Cited by 96 publications

(78 citation statements)

References 33 publications

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“…The artificial incorporation of D-amino acids can also be beneficial. For example, a growing number of synthetic peptides͞peptide libraries containing D-amino acids have been assembled to capitalize on the ability of such residues to provide improved protease stability [enhanced pharmokinetic profile (5-7)], alter tertiary structure (new structural elements can be assembled that cannot be built solely from L-amino acids), and affect the activity of bioactive peptides [enhanced antibacterial activity with concomitant reduction in cell cytotoxicity (5,6,(8)(9)(10)(11)]. …”

mentioning

confidence: 99%

Posttranslational conversion of l -serines to d -alanines is vital for optimal production and activity of the lantibiotic lacticin 3147

Cotter

O’Connor²,

Draper³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

118

146

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As a general rule, ribosomally synthesized polypeptides contain amino acids only in the L-isoform in an order dictated by the coding DNA͞RNA. Two of a total of only four examples of L to D conversions in prokaryotic systems occur in posttranslationally modified antimicrobial peptides called lantibiotics. In both examples (lactocin S and lacticin 3147), ribosomally encoded L-serines are enzymatically converted to D-alanines, giving rise to an apparent mistranslation of serine codons to alanine residues. It has been suggested that this conversion results from a two-step reaction initiated by a lantibiotic synthetase converting the gene-encoded L-serine to dehydroalanine (dha). By using lacticin 3147 as a model system, we report the identification of an enzyme, LtnJ, that is responsible for the conversion of dha to D-alanine. Deletion of this enzyme results in the residues remaining as dha intermediates, leading to a dramatic reduction in the antimicrobial activity of the producing strain. The importance of the chirality of the three D-alanines present in lacticin 3147 was confirmed when these residues were systematically substituted by L-alanines. In addition, substitution with L-threonine (ultimately modified to dehydrobutyrine), glycine, or L-valine also resulted in diminished peptide production and͞or relative activity, the extent of which depended on the chirality of the newly incorporated amino acid(s).antimicrobial ͉ bacteriocin ͉ chirality T he presence of D-amino acids in ribosomally synthesized peptides was first observed in dermorphins, peptides found in the skin secretions of species of a subfamily of South American tree frogs, Phyllomedusinae. Subsequently, D-amino acids have been identified in a number of other ribosomally synthesized peptides of eukaryotic origin (1, 2). -Agatoxin IVb and bombinin H, produced by the funnel-web spider and the skin secretions of the frog Bombina variegata, respectively, represent the only instances in which the responsible enzymes, both peptide epimerases, have been identified (1, 2). For -agatoxin IVb the relevant L-serine to D-serine conversion is thought to involve a deprotonation͞reprotonation reaction (3). The presence of D-amino acids in many of these peptides is crucial, as demonstrated by the creation of synthetic analogues with Lrather than D-amino acids at the relevant locations, which are devoid of activity (4). The artificial incorporation of D-amino acids can also be beneficial. For example, a growing number of synthetic peptides͞peptide libraries containing D-amino acids have been assembled to capitalize on the ability of such residues to provide improved protease stability [enhanced pharmokinetic profile (5-7)], alter tertiary structure (new structural elements can be assembled that cannot be built solely from L-amino acids), and affect the activity of bioactive peptides [enhanced antibacterial activity with concomitant reduction in cell cytotoxicity (5, 6, 8-11)].In prokaryotic systems, there are only a few examples of L-to D-amino acid conversions. It...

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mentioning

confidence: 99%

Posttranslational conversion of l -serines to d -alanines is vital for optimal production and activity of the lantibiotic lacticin 3147

Cotter

O’Connor²,

Draper³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

118

146

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“…Some of the post-translational strategies, such as C-terminal amidation, cyclization, D-amino acid incorporation, and halogenation, have been adopted in laboratories to enhance peptide stability to proteases. As a consequence, several engineered peptides have been demonstrated to be able to keep animal healthy [73][74][75][76][77][78][79][80][81][82][83][84].…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

“…In addition, lactoferricin, distinctin, ranalexin, halocidin, polybia-MPI, chicken cathelicidin 1 (fowlicidin-1), bacterial mutacin B-Ny266, and bacterial ABP-118 have been tested in mice models [73][74][75][76][77][78][79][80]. Other engineered peptides or AMP mimics that have been evaluated in animal models include D, L-peptides, WLBU2, Pro-rich A3-APO, and acyl-lysyl oligomers [81][82][83][84]. Although topical treatments are preferred, an acyl-lysyl compound showed systemic efficacy in a mouse model [84].…”

Section: Therapeutic Potentials Of Ampsmentioning

confidence: 99%

Post-Translational Modifications of Natural Antimicrobial Peptides and Strategies for Peptide Engineering

Wang¹

2011

CBIOT

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Natural antimicrobial peptides (AMPs) are gene-coded defense molecules discovered in all the three life domains: Eubacteria, Archaea, and Eukarya. The latter covers protists, fungi, plants, and animals. It is now recognized that amino acid composition, peptide sequence, and posttranslational modifications determine to a large extent the structure and function of AMPs. This article systematically describes post-translational modifications of natural AMPs annotated in the antimicrobial peptide database (http://aps.unmc.edu/AP). Currently, 1147 out of 1755 AMPs in the database are modified and classified into more than 17 types. Through chemical modifications, the peptides fold into a variety of structural scaffolds that target bacterial surfaces or molecules within cells. Chemical modifications also confer desired functions to a particular peptide. Meanwhile, these modifications modulate other peptide properties such as stability. Elucidation of the relationship between AMP property and chemical modification inspires peptide engineering. Depending on the objective of our design, peptides may be modified in various ways so that the desired features can be enhanced whereas unwanted properties can be minimized. Therefore, peptide design plays an essential role in developing natural AMPs into a new generation of therapeutic molecules.

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“…Mice infected with multi-resistant strains of A. baumanni are often used as model systems to evaluate new drugs and antibiotics (Braunstein et al, 2004;Dijkshoorn et al, 2004;Montero et al, 2004) and Caenorhabditis elegans and Dictyostelium discoideum infected with insertional-mutants are used as virulence assays for assessing the roles played by specific genes in pathogenicity (section 6.1).…”

Section: Non-human Animal Pathogenicitymentioning

confidence: 99%

“…This species caused severe respiratory symptoms in lovebird (Robino et al, 2005), septicaemia in hens (Kaya et al, 1989), bacteriospermia in pigs (Althouse and Lu, 2005) and arthritis in a racing pigeon (Duchatel et al, 2000). The role of A. baumannii as a nosocomial pathogen has also been recognized for dogs, cats and horses in intensive care units (Francey et al, 2000;Boerlin et al, 2001), and as the cause of necrotizing fasciitis and septic shock in a cat (Brachelente et al, 2007).Mice infected with multi-resistant strains of A. baumanni are often used as model systems to evaluate new drugs and antibiotics (Braunstein et al, 2004;Dijkshoorn et al, 2004;Montero et al, 2004) and Caenorhabditis elegans and Dictyostelium discoideum infected with insertional-mutants are used as virulence assays for assessing the roles played by specific genes in pathogenicity (section 6.1).The presence of antibodies to A. calcoaceticus, but not other bacteria, was found in brains of animals suffering from bovine spongiform encephalopathy (BSE) (Tiwana et al, 1999). This was discussed in section 8.6.…”

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confidence: 99%

Safety Assessment of Transgenic Organisms, Volume 4

2010

Harmonisation of Regulatory Oversight in Biotechnology

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In Vitro Activity and Potency of an Intravenously Injected Antimicrobial Peptide and Its dl Amino Acid Analog in Mice Infected with Bacteria

Cited by 96 publications

References 33 publications

Posttranslational conversion of l -serines to d -alanines is vital for optimal production and activity of the lantibiotic lacticin 3147

Posttranslational conversion of l -serines to d -alanines is vital for optimal production and activity of the lantibiotic lacticin 3147

Post-Translational Modifications of Natural Antimicrobial Peptides and Strategies for Peptide Engineering

Safety Assessment of Transgenic Organisms, Volume 4

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