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Structure-Activity Relationships of the Antimicrobial Peptide Natural Product Apidaecin.

ABSTRACT: With the growing crisis of antimicrobial resistance, it is critical to continue to seek out new sources of novel antibiotics. This need has led to renewed interest in natural product antimicrobials, specifically antimicrobial peptides. Nonlytic antimicrobial peptides are highly promising due to their unique mechanisms of action. One such peptide is apidaecin (Api), which inhibits translation termination through stabilization of the quaternary complex of the ribosome-apidaecin-tRNA-release factor. Synthetic derivatives of apidaecin have been developed, but structure-guided modifications have yet to be considered. In this work, we have focused on modifying key residues in the Api sequence that are responsible for the interactions that stabilize the quaternary complex. We present one of the first examples of a highly modified Api peptide that maintains its antimicrobial activity and interaction with the translation complex. These findings establish a starting point for further structure-guided optimization of Api peptides.

SUBMITTER: Skowron KJ

PROVIDER: S-EPMC10768847 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Structure-Activity Relationships of the Antimicrobial Peptide Natural Product Apidaecin.

Skowron Kornelia J KJ Baliga Chetana C Johnson Tatum T Kremiller Kyle M KM Castroverde Alexandra A Dean Trevor T TT Allen A'Lester C AC Lopez-Hernandez Ana M AM Aleksandrova Elena V EV Klepacki Dorota D Mankin Alexander S AS Polikanov Yury S YS Moore Terry W TW

Journal of medicinal chemistry 20230821 17

With the growing crisis of antimicrobial resistance, it is critical to continue to seek out new sources of novel antibiotics. This need has led to renewed interest in natural product antimicrobials, specifically antimicrobial peptides. Nonlytic antimicrobial peptides are highly promising due to their unique mechanisms of action. One such peptide is apidaecin (Api), which inhibits translation termination through stabilization of the quaternary complex of the ribosome-apidaecin-tRNA-release factor ...[more]

PMID: 37603874

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Project description:Proline-rich antimicrobial peptide apidaecin (Api) inhibits bacterial protein synthesis in a distinctive way. In vitro biochemical and structural studies showed that Api binds in the nascent peptide exit tunnel of the ribosome that has completed translation of the gene and has released the newly-synthesized protein. Once in the tunnel, Api traps the release factors on the post-termination ribosome leading to cessation of translation. The mode of Api action in the bacterial cell, however, had remained unknow. By analyzing distribution of ribosomes on mRNAs in Api-treated cells using Ribo-seq approach we uncovered a range of effects that stem from the unique mechanism of Api action. Exposure of bacterial cells to Api results in arrest of translation at stop codons, likely in a post-release state, due to the immediate Api action, as well as in a pre-release state due to the depletion of available release factors. In addition, arrest of translation at the end of the open reading frame (ORF) leads to a pronounced queuing of the translating ribosomes behind the one arrested at the stop codon. One of the major consequences of the Api action is a dramatically increased stop codon bypass by the ribosomes paused in a pre-release state, leading to accumulation of proteins with C-terminal extensions, as confirmed by whole-cell proteomics analysis. Stop codon bypass, that occurs either in 0-frame, by misincorporation of a near-cognate aminoacyl-tRNA at the stop codon, or via frameshifting allows for a fraction of the translating ribosomes to reach the 3’ ends of mRNA transcripts. The pervasive stalling of pre-release ribosomes at the stop codons and at the RNA transcripts ends triggers activation of the cellular ribosome rescue systems which, likely due to Api action as well, remain ineffective. While major Api effects are directed towards the ribosome at the end of the ORFs, cells exposed to Api show a somewhat increased ribosome occupancy of the start codons. Understanding the unique mode of Api to inhibit translation termination in the cell can help envisioning the development of treatments for genetic diseases and research tools for genome exploration.

Dataset Information

Structure-Activity Relationships of the Antimicrobial Peptide Natural Product Apidaecin.

Publications

Structure-Activity Relationships of the Antimicrobial Peptide Natural Product Apidaecin.

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