Publications by authors named "Chad W Johnston"
Despite decades of study, large parts of the mammalian metabolome remain unexplored. Mass spectrometry-based metabolomics routinely detects thousands of small molecule-associated peaks within human tissues and biofluids, but typically only a small fraction of these can be identified, and structure elucidation of novel metabolites remains a low-throughput endeavor. Biochemical large language models have transformed the interpretation of DNA, RNA, and protein sequences, but have not yet had a comparable impact on understanding small molecule metabolism.
View Article and Find Full Text PDFNatural and engineered precision antibiotics in the context of resistance.
Curr Opin Chem Biol
August 2022
Article Synopsis
- - Antibiotics are crucial for treating infections, but their broad use may harm the body's microbiome and lead to drug resistance, sparking interest in more targeted alternatives.
- - Precision antibiotics are being developed to treat infections effectively while minimizing damage to beneficial bacteria and slowing down resistance, similar to the trend in precision medicine for cancer.
- - This text highlights the potential of rediscovering natural antibacterial compounds and engineering strategies to create drugs that specifically target pathogens without disrupting the microbiome.
Article Synopsis
- Novel antibiotics are urgently needed due to the global issue of antibiotic resistance, with most existing ones coming from microbial secondary metabolism.
- PRISM 4 is a new platform that predicts the chemical structures of antibiotics encoded in bacterial genomes, helping to find new natural antibiotics.
- The platform has been used to analyze over 10,000 bacterial genomes, uncovering thousands of potential new antibiotics, and is accessible for free online.
Article Synopsis
- - Antibiotic biosynthetic gene clusters (BGCs) produce metabolites that help the producer survive, playing a key role in the evolution of antibiotics.
- - Researchers utilized phage-assisted continuous evolution (PACE) to adapt the gene cluster for bicyclomycin (BCM), enhancing its production in a different organism.
- - This study highlights how mimicking natural evolution can lead to innovative strategies for improving metabolic pathways and increasing the yield of antibiotic production.
Article Synopsis
- - The study focuses on tRNA-derived cyclodipeptides, which are small molecules known for their beneficial biological activities, but there's a lack of tools to connect specific synthases in bacteria to the cyclodipeptides they produce.
- - Researchers developed a new pipeline to identify and classify gene clusters related to cyclodipeptides across over 93,000 prokaryotic genomes, helping to predict what these peptides might look like and how they’re made.
- - Their findings reveal a significant amount of unexplored chemical potential within prokaryotic genomes, and the created mapping tool serves as a resource for discovering new cyclodipeptides in future research.
Article Synopsis
- Microbial natural products are valuable for pharmaceuticals and industry, but many remain undiscovered due to complex biosynthetic gene clusters.
- The PRISM (PRediction Informatics for Secondary Metabolomes) project has been revamped with a new algorithm (PRISM 3) that models natural products as chemical graphs, predicting structures for various compounds and expanding to 22 cluster types.
- Key improvements in PRISM 3 include enhanced user experience, faster processing on a large server grid, and better detection of genetic sequences, making natural product discovery more efficient.
Article Synopsis
- * Despite genome sequencing showing many genetically encoded natural products are still unknown, existing bioinformatics tools have been developed to predict nonribosomal peptides and polyketides from sequence data, while RiPPs remain poorly understood due to their complexity.
- * The study introduces a new algorithm that catalogs RiPP biosynthetic gene clusters, uncovering 30,261 RiPP clusters from over 65,000 prokaryotic genomes, leading to the identification of a rare
Article Synopsis
- - Polyketides (PKs) and nonribosomal peptides (NRPs) are vital natural products and form the basis for many important therapies, with over 11,000 known structures identified through past research.
- - While genome sequencing is revealing new PK and NRP gene clusters rapidly, only about 10% are linked to specific molecules, leaving many "orphan" clusters uncharacterized.
- - The study introduces two new tools: the generalized retro-biosynthetic assembly prediction engine (GRAPE) and the global alignment for natural products cheminformatics (GARLIC), aimed at systematically identifying orphan gene clusters and predicting their associated molecules.
Background & Aims: Partially degraded gluten peptides from cereals trigger celiac disease (CD), an autoimmune enteropathy occurring in genetically susceptible persons. Susceptibility genes are necessary but not sufficient to induce CD, and additional environmental factors related to unfavorable alterations in the microbiota have been proposed. We investigated gluten metabolism by opportunistic pathogens and commensal duodenal bacteria and characterized the capacity of the produced peptides to activate gluten-specific T-cells from CD patients.
View Article and Find Full Text PDFArticle Synopsis
- Streptomyces silvensis produces nonribosomal peptides that inhibit human oxytocin and vasopressin receptors.
- The genome sequence of S. silvensis ATCC 53525 was analyzed and found to contain multiple biosynthetic gene clusters.
- This organism shows potential as a valuable resource for developing new drugs through genome-guided discovery.
Article Synopsis
- * New microbial sources need to be identified to innovate therapeutic and industrial compounds, as much of the microbial diversity is still unexplored.
- * This research highlights a specific genus with diverse biosynthetic capabilities, leading to the discovery of a novel polyketide surfactant, showcasing its potential for generating new chemical scaffolds.
Article Synopsis
- Antibiotics are crucial for treating bacterial infections, but their overuse has caused resistance, leading to a need for new antibacterial agents with different targets.
- Most current antibacterial drugs come from natural products found in microbes, but there's a lack of organization in this data, hindering research efforts.
- The study introduces a new resource to classify natural antibacterials and applies a method to uncover previously unknown antibacterial mechanisms, finding that telomycin from Streptomyces canus works through a unique target related to bacterial phospholipids.
Article Synopsis
- Microbial natural products are key sources of bioactive compounds but face challenges due to the high rediscovery of known metabolites in traditional screening methods.
- PRISM is a new computational tool that identifies biosynthetic gene clusters and predicts novel chemical structures like nonribosomal peptides and polyketides, enhancing the search for new natural products.
- It offers a user-friendly, open-source platform with advanced algorithms for accurate predictions, available online for researchers to utilize.
Article Synopsis
- * A new automated tool has been developed that uses genome sequencing data to predict and identify valuable compounds like polyketides and nonribosomal peptides from these bacterial genomes.
- * This tool has successfully identified and isolated six predicted compounds, showcasing its effectiveness and potential for discovering genetically encoded natural products.
Article Synopsis
- - Microbial natural products are crucial in pharmaceuticals due to their diverse chemical structures, and the study introduces an untargeted metabolomics algorithm based on the iSNAP platform that enhances identification of peptide natural products.
- - The algorithm analyzes mass spectrometry data using known structures to uncover extensive molecular families in crude microbial extracts, achieving high confidence in results.
- - The research highlights a significant number of previously unreported natural product variants, including a new variant that has increased potency, showcasing the iSNAP platform's effectiveness in profiling nonribosomal peptides.
Informatic search strategies to discover analogues and variants of natural product archetypes.
J Ind Microbiol Biotechnol
March 2016
Article Synopsis
- - Natural products are important for finding new antimicrobials, but current methods of discovery are becoming less effective, leading to reduced interest.
- - The researchers utilized automated informatic platforms to focus on biologically active natural products, particularly a group called peptaibols.
- - By applying mass spectrometry and specialized software, they successfully detected and analyzed natural product variants, revealing new opportunities for developing pharmaceutical agents from these natural compounds.
Article Synopsis
- * Researchers have developed an improved informatic search algorithm called iSNAP, which helps identify both known and predicted depsipeptides in complex microbial cultures.
- * The study successfully identified new depsipeptides and gene clusters for future research, showcasing the effectiveness of chemoinformatic methods in discovering genetically encoded metabolites.
Article Synopsis
- Natural lipocyclocarbamate compounds have inspired the development of darapladib, a novel synthetic drug aimed at inhibiting phospholipase activity.
- Darapladib is currently undergoing phase III clinical trials to evaluate its effectiveness in treating atherosclerosis.
- The synthesis of these natural products is facilitated by a process involving nonribosomal peptide synthetase.
Article Synopsis
- Microorganisms create and release secondary metabolites to help them survive in their environments.
- Delftia acidovorans, a bacterium found in gold environments, produces a secondary metabolite that safeguards it from harmful soluble gold by turning it into solid gold forms.
- This is the first evidence showing that a metabolite can protect against toxic gold and lead to the formation of gold in solid form through biomineralization.