Dataset Information

Incorporation of ?-Amino Acids Enhances the Antifungal Activity and Selectivity of the Helical Antimicrobial Peptide Aurein 1.2.

ABSTRACT: Antimicrobial peptides (AMPs) are attractive antifungal drug candidates because they kill microbes via membrane disruption and are thus unlikely to provoke development of resistance. Low selectivity for fungal vs human cells and instability in physiological environments have limited the development of AMPs as therapeutics, but peptidomimetic AMPs can overcome these obstacles and also provide useful insight into AMP structure-function relationships. Here, we describe antifungal peptidomimetic ?/?-peptides templated on the natural ?-peptidic AMP aurein 1.2. These ?/?-aurein analogs fold into i ? i + 4 H-bonded helices that present arrays of side chain functionality in a manner virtually identical to that of aurein 1.2. By varying charge, hydrophobicity, conformational stability, and ?/?-amino acid organization, we designed active and selective ?/?-peptide aurein analogs that exhibit minimum inhibitory concentrations (MIC) against the opportunistic pathogen Candida albicans that are 4-fold lower than that of aurein 1.2 and elicit less than 5% hemolysis at the MIC. These ?/?-aurein analogs are promising candidates for development as antifungal therapeutics and as tools to elucidate mechanisms of AMP activity and specificity.

SUBMITTER: Lee MR

PROVIDER: S-EPMC5732081 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Incorporation of β-Amino Acids Enhances the Antifungal Activity and Selectivity of the Helical Antimicrobial Peptide Aurein 1.2.

Lee Myung-Ryul MR Raman Namrata N Gellman Samuel H SH Lynn David M DM Palecek Sean P SP

ACS chemical biology 20171130 12

Antimicrobial peptides (AMPs) are attractive antifungal drug candidates because they kill microbes via membrane disruption and are thus unlikely to provoke development of resistance. Low selectivity for fungal vs human cells and instability in physiological environments have limited the development of AMPs as therapeutics, but peptidomimetic AMPs can overcome these obstacles and also provide useful insight into AMP structure-function relationships. Here, we describe antifungal peptidomimetic α/β ...[more]

PMID: 29091404

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Project description:Nature has a variety of possibilities to create new protein functions by modifying the sequence of the individual amino acid building blocks. However, all variations are based on the 20 canonical amino acids (cAAs). As a way to introduce additional physicochemical properties into polypeptides, the incorporation of non-canonical amino acids (ncAAs) is increasingly used in protein engineering. Due to their relatively short length, the modification of ribosomally synthesized and post-translationally modified peptides by ncAAs is particularly attractive. New functionalities and chemical handles can be generated by specific modifications of individual residues. The selective pressure incorporation (SPI) method utilizes auxotrophic host strains that are deprived of an essential amino acid in chemically defined growth media. Several structurally and chemically similar amino acid analogs can then be activated by the corresponding aminoacyl-tRNA synthetase and provide residue-specific cAA(s) → ncAA(s) substitutions in the target peptide or protein sequence. Although, in the context of the SPI method, ncAAs are also incorporated into the host proteome during the phase of recombinant gene expression, the majority of the cell's resources are assigned to the expression of the target gene. This enables efficient residue-specific incorporation of ncAAs often accompanied with high amounts of modified target. The presented work describes the in vivo incorporation of six proline analogs into the antimicrobial peptide nisin, a lantibiotic naturally produced by Lactococcus lactis. Antimicrobial properties of nisin can be changed and further expanded during its fermentation and expression in auxotrophic Escherichia coli strains in defined growth media. Thereby, the effects of residue-specific replacement of cAAs with ncAAs can deliver changes in antimicrobial activity and specificity. Antimicrobial activity assays and fluorescence microscopy are used to test the new nisin variants for growth inhibition of a Gram-positive Lactococcus lactis indicator strain. Mass spectroscopy is used to confirm ncAA incorporation in bioactive nisin variants.

Dataset Information

Incorporation of ?-Amino Acids Enhances the Antifungal Activity and Selectivity of the Helical Antimicrobial Peptide Aurein 1.2.

Publications

Incorporation of β-Amino Acids Enhances the Antifungal Activity and Selectivity of the Helical Antimicrobial Peptide Aurein 1.2.

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