Discovery and characterization of ribosomally synthesized and post-translationally modified peptide natural products
type: CreativeWork
description: Bacterial secondary metabolites have historically been a rich source of antibiotic compounds. The genomic era has shown that bacteria harbor the potential to produce even more natural products that could be developed into new antibiotic agents to combat the alarming rise in antibiotic- resistant pathogens. Ribosomally synthesized and post-translationally modified peptide (RiPP) natural products are genetically encoded peptide-derived secondary metabolites whose structures can be predicted based on gene sequence and identity of tailoring enzymes within the biosynthetic gene cluster. Post-translational modifications installed by the tailoring enzymes in a site-selective manner endow the compounds with structural rigidity and, in many cases, interesting biological activities. Once genome mining has been used to select RiPPs gene clusters, chemical and microbiological techniques are employed to characterize the structure, biosynthesis, antibiotic activity, and mode of action of newly discovered RiPPs. Plantazolicin (PZN) is a RiPP natural product with a rigid, polyheterocyclic structure and a remarkably species-specific antibiotic activity, targeting the pathogen Bacillus anthracis. While the highly modified natural product bears the characteristic heterocycles of a linear azol(in)e- containing RiPP, N-terminal dimethylation after cleavage of the leader peptide is also essential for bioactivity. The methyltransferase responsible for this post-translational modification is highly evolved for PZN-like substrates, with very little tolerance to mutant sequences. The underlying cause of the ultra-narrow spectrum bioactivity was investigated using a broad range of chemical and microbiological techniques. PZN was not found to have a proteinaceous target; instead, the bioactivity was found to be dependent on the diphosphatidylglycerol lipid cardiolipin. PZN is thought to localize to weakened sections of the B. anthracis membrane that contain aggregates of cardiolipin. These lip…
abstract: Bacterial secondary metabolites have historically been a rich source of antibiotic compounds. The genomic era has shown that bacteria harbor the potential to produce even more natural products that could be developed into new antibiotic agents to combat the alarming rise in antibiotic- resistant pathogens. Ribosomally synthesized and post-translationally modified peptide (RiPP) natural products are genetically encoded peptide-derived secondary metabolites whose structures can be predicted based on gene sequence and identity of tailoring enzymes within the biosynthetic gene cluster. Post-translational modifications installed by the tailoring enzymes in a site-selective manner endow the compounds with structural rigidity and, in many cases, interesting biological activities. Once genome mining has been used to select RiPPs gene clusters, chemical and microbiological techniques are employed to characterize the structure, biosynthesis, antibiotic activity, and mode of action of newly discovered RiPPs. Plantazolicin (PZN) is a RiPP natural product with a rigid, polyheterocyclic structure and a remarkably species-specific antibiotic activity, targeting the pathogen Bacillus anthracis. While the highly modified natural product bears the characteristic heterocycles of a linear azol(in)e- containing RiPP, N-terminal dimethylation after cleavage of the leader peptide is also essential for bioactivity. The methyltransferase responsible for this post-translational modification is highly evolved for PZN-like substrates, with very little tolerance to mutant sequences. The underlying cause of the ultra-narrow spectrum bioactivity was investigated using a broad range of chemical and microbiological techniques. PZN was not found to have a proteinaceous target; instead, the bioactivity was found to be dependent on the diphosphatidylglycerol lipid cardiolipin. PZN is thought to localize to weakened sections of the B. anthracis membrane that contain aggregates of cardiolipin. These lip…
author: Blair, Patricia M
language: en
keywords: Ribosomally synthesized and post-translationally modified peptide, Natural products, Chemical probes, Mode of action
date published: 2017-03-01T16:36:51Z
date modified: 2026-07-22T22:26:37Z
provider: University of Illinois - Urbana-Champaign
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Illinois at Urbana-Champaign

PropertyValue
property ID: Handle
value: http://hdl.handle.net/2142/95476