2024
Mucosal sugars delineate pyrazine vs pyrazinone autoinducer signaling in Klebsiella oxytoca
Hamchand R, Wang K, Song D, Palm N, Crawford J. Mucosal sugars delineate pyrazine vs pyrazinone autoinducer signaling in Klebsiella oxytoca. Nature Communications 2024, 15: 8902. PMID: 39406708, PMCID: PMC11480411, DOI: 10.1038/s41467-024-53185-6.Peer-Reviewed Original ResearchConceptsK. oxytocaGeneral carbohydrate metabolismVirulence factor productionPLP-dependent enzymesAssociated with gutEnterobactin biosynthesisAutoinducer signalBacterial virulenceKlebsiella oxytocaSpecific carbohydratesHost immune responseCarbohydrate metabolismAutoinducerMolecular signalsVirulenceHistamine receptor H4BiosynthesisHost signalAcquisition responsesProtease inhibitorsPathwayHostLung pathologyLung isolationImmune response
2022
Cellular Stress-Induced Metabolites in Escherichia coli
Gatsios A, Kim C, York A, Flavell R, Crawford J. Cellular Stress-Induced Metabolites in Escherichia coli. Journal Of Natural Products 2022, 85: 2626-2640. PMID: 36346625, PMCID: PMC9949963, DOI: 10.1021/acs.jnatprod.2c00706.Peer-Reviewed Original ResearchCross-kingdom expression of synthetic genetic elements promotes discovery of metabolites in the human microbiome
Patel JR, Oh J, Wang S, Crawford JM, Isaacs FJ. Cross-kingdom expression of synthetic genetic elements promotes discovery of metabolites in the human microbiome. Cell 2022, 185: 1487-1505.e14. PMID: 35366417, PMCID: PMC10619838, DOI: 10.1016/j.cell.2022.03.008.Peer-Reviewed Original ResearchConceptsSynthetic genetic elementsGenetic elementsBiosynthetic gene clusterCross-species expressionCross-species interactionsDiverse organismsGene clusterBiosynthetic machineryHeterologous expressionRegulatory regionsTRNA synthetasesBiosynthetic pathwayNative contextTranslational activityBiosynthetic capacityHuman microbiomeMetabolic capacityPositive bacteriaSmall moleculesExpressionPathwayValuable compoundsLactobacillus inersEukaryotesSynthetases
2021
Escherichia coli-Derived γ‑Lactams and Structurally Related Metabolites Are Produced at the Intersection of Colibactin and Fatty Acid Biosynthesis
Kim CS, Turocy T, Moon G, Shine EE, Crawford JM. Escherichia coli-Derived γ‑Lactams and Structurally Related Metabolites Are Produced at the Intersection of Colibactin and Fatty Acid Biosynthesis. Organic Letters 2021, 23: 6895-6899. PMID: 34406772, PMCID: PMC10577019, DOI: 10.1021/acs.orglett.1c02461.Peer-Reviewed Original ResearchConceptsFatty acid biosynthesisAcid biosynthesisHybrid polyketide-nonribosomal peptideNuclear magnetic resonance spectroscopyΓ-lactam derivativesUnknown biological activityBiosynthetic logicMagnetic resonance spectroscopyCancer initiationColorectal cancer initiationStereochemical analysisΓ-lactamsColibactinResonance spectroscopyDiverse collectionBiosynthesisBiological activityAbundant metabolitesPathwayRelated metabolitesRelated structuresMetabolitesLociProteinSpectroscopy
2020
Structure and bioactivity of colibactin
Wernke KM, Xue M, Tirla A, Kim CS, Crawford JM, Herzon SB. Structure and bioactivity of colibactin. Bioorganic & Medicinal Chemistry Letters 2020, 30: 127280. PMID: 32527463, PMCID: PMC7309967, DOI: 10.1016/j.bmcl.2020.127280.Peer-Reviewed Original ResearchConceptsColibactin-producing bacteriaStrands of DNABiosynthetic pathwaySecondary metabolitesColibactinMolecular-level explanationHuman gutAdenine residuesCell contactElectrophilic CyclopropanesCertain strainsBacteriaGenotoxic effectsHeterodimersDNABacterial cultureResiduesPathwayCleavageCellsStrandsGut
2017
Structure and Functional Analysis of ClbQ, an Unusual Intermediate-Releasing Thioesterase from the Colibactin Biosynthetic Pathway
Guntaka NS, Healy AR, Crawford JM, Herzon SB, Bruner SD. Structure and Functional Analysis of ClbQ, an Unusual Intermediate-Releasing Thioesterase from the Colibactin Biosynthetic Pathway. ACS Chemical Biology 2017, 12: 2598-2608. PMID: 28846367, PMCID: PMC5830302, DOI: 10.1021/acschembio.7b00479.Peer-Reviewed Original ResearchConceptsColibactin gene clusterÅ crystal structurePolyketide secondary metabolitesAcyl-thioester substratesColibactin biosynthesisGene clusterBiosynthetic pathwayAtypical roleGene productsBiochemical characterizationFunctional analysisSecondary metabolitesGreater catalytic efficiencyCancer formationColorectal cancer formationHuman gutSpecific functionsNovel insightsCarrier proteinThioesteraseGenetic deletionClbQColibactinCatalytic efficiencyPathwayDomain-Targeted Metabolomics Delineates the Heterocycle Assembly Steps of Colibactin Biosynthesis
Trautman EP, Healy AR, Shine EE, Herzon SB, Crawford JM. Domain-Targeted Metabolomics Delineates the Heterocycle Assembly Steps of Colibactin Biosynthesis. Journal Of The American Chemical Society 2017, 139: 4195-4201. PMID: 28240912, PMCID: PMC5831107, DOI: 10.1021/jacs.7b00659.Peer-Reviewed Original ResearchConceptsNonribosomal peptide synthetasesPolyketide synthasesModular polyketide synthasesSite-directed mutagenesisCombination of genesCellular metabolic levelsColibactin biosynthesisMultidomain proteinsProtein domainsPeptide synthetasesCatalytic domainControl pathwaysProtein biochemicalPathway analysisCertain Escherichia coliComplete deletionHybrid pathwayEscherichia coliFunctional readoutBiosynthesisCatalytic mechanismCellular levelMetabolic levelPathwayGenesAcyl Histidines: New N‐Acyl Amides from Legionella pneumophila
Tørring T, Shames SR, Cho W, Roy CR, Crawford JM. Acyl Histidines: New N‐Acyl Amides from Legionella pneumophila. ChemBioChem 2017, 18: 638-646. PMID: 28116768, PMCID: PMC5546091, DOI: 10.1002/cbic.201600618.Peer-Reviewed Original ResearchConceptsBiosynthetic gene clusterOrphan biosynthetic gene clustersPathogen-insect interactionsAmino acid-derived metabolitesLegionella pneumophilaOrphan pathwaysBiosynthetic genesVariety of protozoanGene clusterN-acyl amidesMolecular networkingHuman macrophagesDistinct groupsPneumophilaCausative agentPathwayMetabolitesHistidine metabolitesNew N-acylGenesLegionnaires' diseaseAmoebaeProtozoaMacrophagesPathogens
2016
Activating and Attenuating the Amicoumacin Antibiotics
Park HB, Perez CE, Perry EK, Crawford JM. Activating and Attenuating the Amicoumacin Antibiotics. Molecules 2016, 21: 824. PMID: 27347911, PMCID: PMC5055758, DOI: 10.3390/molecules21070824.Peer-Reviewed Original ResearchLinking Biosynthetic Gene Clusters to their Metabolites via Pathway-Targeted Molecular Networking
Trautman EP, Crawford JM. Linking Biosynthetic Gene Clusters to their Metabolites via Pathway-Targeted Molecular Networking. Current Topics In Medicinal Chemistry 2016, 16: 1705-1716. PMID: 26456470, PMCID: PMC5055756, DOI: 10.2174/1568026616666151012111046.Peer-Reviewed Original ResearchConceptsBiosynthetic gene clusterGene clusterMicrobial biosynthetic gene clustersMetabolic pathwaysGenome sequence informationSecondary metabolic pathwaysMolecular networkingHuman-microbe interactionsNew metabolic pathwaysComplex metabolomeSmall moleculesBiosynthetic logicActive small moleculesFunctional characterizationBioinformatics predictionSequence informationSmall molecule metabolitesHuman microbiomeExperimental structural characterizationGut bacteriaPathwayNatural productsMetabolitesPharmacological potentialAvailable databases
2015
The colibactin warhead crosslinks DNA
Vizcaino MI, Crawford JM. The colibactin warhead crosslinks DNA. Nature Chemistry 2015, 7: 411-417. PMID: 25901819, PMCID: PMC4499846, DOI: 10.1038/nchem.2221.Peer-Reviewed Original ResearchConceptsDNA-damaging activityHost-microbe interactionsUncharacterized familyColibactin biosynthesisSmall moleculesHybrid pathwayCancer formationMode of actionDuplex DNACrosslinks DNAMicrobial metabolitesUnexpected modelHuman microbiotaSelect strainsMetabolomic analysisDNAPathwayEscherichia coli presentHuman colonLabeling studiesDisease statesDirect experimental evidenceHuman healthBiosynthesisColibactin
2014
An Atypical Orphan Carbohydrate-NRPS Genomic Island Encodes a Novel Lytic Transglycosylase
Guo X, Crawford JM. An Atypical Orphan Carbohydrate-NRPS Genomic Island Encodes a Novel Lytic Transglycosylase. Cell Chemical Biology 2014, 21: 1271-1277. PMID: 25219963, PMCID: PMC4224617, DOI: 10.1016/j.chembiol.2014.07.025.Peer-Reviewed Original ResearchConceptsGenome synteny analysisSynteny analysisGenomic islandsLytic transglycosylaseNatural product gene clustersOrphan biosynthetic pathwaysGene deletion analysisGenome sequencing platformsRare structural featureBiochemical reconstructionHypothetical proteinsGene clusterAcetyl-glucosamine moietyHeterologous expressionDeletion analysisProtein homologyBiosynthetic pathwayIsland contentNew small moleculesSequencing platformsMetabolic chemistryTransglycosylasePathwaySmall moleculesNatural productsComparative Metabolomics and Structural Characterizations Illuminate Colibactin Pathway-Dependent Small Molecules
Vizcaino MI, Engel P, Trautman E, Crawford JM. Comparative Metabolomics and Structural Characterizations Illuminate Colibactin Pathway-Dependent Small Molecules. Journal Of The American Chemical Society 2014, 136: 9244-9247. PMID: 24932672, PMCID: PMC4091280, DOI: 10.1021/ja503450q.Peer-Reviewed Original ResearchConceptsReceptor antagonist activityE. coli Nissle 1917Coli Nissle 1917Ulcerative colitisInflammatory conditionsProbiotic E. coli Nissle 1917Human bowelPathogenic Escherichia coliAntagonist activityNissle 1917Growth inhibitoryCarcinogenic activityProbiotic activitySmall moleculesPathwayStructural network analysisColitisBowelComparative metabolomicsPersistence phenotypeMetabolomics
2008
Acyl‐Carrier Protein–Phosphopantetheinyltransferase Partnerships in Fungal Fatty Acid Synthases
Crawford JM, Vagstad AL, Ehrlich KC, Udwary DW, Townsend CA. Acyl‐Carrier Protein–Phosphopantetheinyltransferase Partnerships in Fungal Fatty Acid Synthases. ChemBioChem 2008, 9: 1559-1563. PMID: 18551496, PMCID: PMC3189688, DOI: 10.1002/cbic.200700659.Peer-Reviewed Original ResearchStarter unit specificity directs genome mining of polyketide synthase pathways in fungi
Crawford JM, Vagstad AL, Ehrlich KC, Townsend CA. Starter unit specificity directs genome mining of polyketide synthase pathways in fungi. Bioorganic Chemistry 2008, 36: 16-22. PMID: 18215412, PMCID: PMC3200548, DOI: 10.1016/j.bioorg.2007.11.002.Peer-Reviewed Original ResearchConceptsHybrid metabolitesPathogenic fungus Coccidioides immitisPolyketide synthase pathwayHuman fungal pathogenSAT domainAflatoxin clusterGenome miningSynthase subunitsPolyketide synthasePKS clustersACP domainStarter unitProtein databasePolyketide synthesisFungal pathogensFunctional similarityHexanoyl-CoA.Fatty acid productsEscherichia coliSynthase pathwayFungiFungus Coccidioides immitisAspergillus speciesPathwayDomain