2022
N‐Acyl Amides from Neisseria meningitidis and Their Role in Sphingosine Receptor Signaling
Cho W, York AG, Wang R, Wyche TP, Piizzi G, Flavell RA, Crawford JM. N‐Acyl Amides from Neisseria meningitidis and Their Role in Sphingosine Receptor Signaling. ChemBioChem 2022, 23: e202200490-e202200490. PMID: 36112057, PMCID: PMC9762135, DOI: 10.1002/cbic.202200490.Peer-Reviewed Original ResearchConceptsN-acyl amidesGram-negative opportunistic pathogenNeisseria meningitidisHuman-associated bacteriaBlood-brain barrierBioactive small moleculesInterleukin-10 signalingMacrophage cell typesN-acyltransferaseInterleukin-17AG proteinsHuman diseasesT cellsReceptor signalingCell typesImmune systemHigh mortalityHuman microbiotaRepresentative membersOpportunistic pathogenMeningitidisSignalingSmall moleculesN.MeningitisCross-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
Molecules from the Microbiome
Shine EE, Crawford JM. Molecules from the Microbiome. Annual Review Of Biochemistry 2021, 90: 1-27. PMID: 33770448, DOI: 10.1146/annurev-biochem-080320-115307.Peer-Reviewed Original ResearchConceptsHuman microbiomeSpecific microbial moleculesSmall moleculesSecond genomeEcological nichesSpecies compositionGenetic capacityInteraction networksMicrobial moleculesMicrobiome editingBiochemical complexitySynthetic biologyMolecular mechanismsHuman cellsImmune system developmentChemical biologyFunctional interactionMicrobiomeDetailed mechanistic studiesBiologyHost responseMechanistic studiesGenomeMoleculesMicrobes
2020
Making and Breaking Leupeptin Protease Inhibitors in Pathogenic Gammaproteobacteria
Li J, Oh J, Kienesberger S, Kim N, Clarke D, Zechner E, Crawford J. Making and Breaking Leupeptin Protease Inhibitors in Pathogenic Gammaproteobacteria. Angewandte Chemie 2020, 132: 18028-18036. DOI: 10.1002/ange.202005506.Peer-Reviewed Original ResearchBacterial small moleculesTripeptide aldehyde protease inhibitorsHeterologous expression analysisProtease inhibitorsPhotorhabdus speciesColonization phenotypesHypothetical proteinsNematode hostsPathogenic GammaproteobacteriaExpression analysisBacterial productionAccessory enzymesGenetic distributionProteolytic degradationSmall moleculesEnzymeLeupeptinKlebsiella oxytocaInhibitorsLigasesXenorhabdusGammaproteobacteriaPhotorhabdusBiosynthesisSpeciesMaking and Breaking Leupeptin Protease Inhibitors in Pathogenic Gammaproteobacteria
Li J, Oh J, Kienesberger S, Kim NY, Clarke DJ, Zechner EL, Crawford J. Making and Breaking Leupeptin Protease Inhibitors in Pathogenic Gammaproteobacteria. Angewandte Chemie International Edition 2020, 59: 17872-17880. PMID: 32609431, DOI: 10.1002/anie.202005506.Peer-Reviewed Original ResearchConceptsBacterial small moleculesTripeptide aldehyde protease inhibitorsHeterologous expression analysisProtease inhibitorsColonization phenotypesPhotorhabdus speciesHypothetical proteinsNematode hostsPathogenic GammaproteobacteriaExpression analysisBacterial productionAccessory enzymesGenetic distributionProteolytic degradationSmall moleculesEnzymeLeupeptinKlebsiella oxytocaInhibitorsGammaproteobacteriaLigasesXenorhabdusPhotorhabdusBiosynthesisSpeciesCellular Stress Upregulates Indole Signaling Metabolites in Escherichia coli
Kim CS, Li JH, Barco B, Park HB, Gatsios A, Damania A, Wang R, Wyche TP, Piizzi G, Clay NK, Crawford JM. Cellular Stress Upregulates Indole Signaling Metabolites in Escherichia coli. Cell Chemical Biology 2020, 27: 698-707.e7. PMID: 32243812, PMCID: PMC7306003, DOI: 10.1016/j.chembiol.2020.03.003.Peer-Reviewed Original ResearchConceptsPlant-pathogen defense responsesPlant innate immune responsesPathogen defense responsesSmall molecule signalsEscherichia coliPersister cell formationStress-induced metabolitesPrimary human tissuesDefense responsesRedox stressorsInnate immune responseDistinct immunological responsesMolecule signalsMolecular studiesCell formationColiBacterial metabolitesDefensive responsesSmall moleculesPlantsHuman tissuesImmune responseImmunological responseInfection modelMetabolites
2019
Bright Green Biofluorescence in Sharks Derives from Bromo-Kynurenine Metabolism
Park HB, Lam YC, Gaffney JP, Weaver JC, Krivoshik SR, Hamchand R, Pieribone V, Gruber DF, Crawford JM. Bright Green Biofluorescence in Sharks Derives from Bromo-Kynurenine Metabolism. IScience 2019, 19: 1291-1336. PMID: 31402257, PMCID: PMC6831821, DOI: 10.1016/j.isci.2019.07.019.Peer-Reviewed Original ResearchGreen fluorescent proteinGFP-like proteinsSpecies of sharksAcid-binding proteinFluorescence microscopy studiesFatty acid-binding proteinUndescribed groupSmall molecule metabolitesLuminescent phenotypeFluorescent proteinProteinMicrobial infectionsBiofluorescenceMarine environmentSharksSmall moleculesStructural detailsDiscovery of metabolitesWidespread natureCentral nervous systemNervous systemSpectral characterizationSpeciesMetabolitesDiversityA Forward Chemical Genetic Screen Reveals Gut Microbiota Metabolites That Modulate Host Physiology
Chen H, Nwe PK, Yang Y, Rosen CE, Bielecka AA, Kuchroo M, Cline GW, Kruse AC, Ring AM, Crawford JM, Palm NW. A Forward Chemical Genetic Screen Reveals Gut Microbiota Metabolites That Modulate Host Physiology. Cell 2019, 177: 1217-1231.e18. PMID: 31006530, PMCID: PMC6536006, DOI: 10.1016/j.cell.2019.03.036.Peer-Reviewed Original ResearchConceptsHost physiologyBioactive microbial metabolitesHuman gut bacteriaHost sensingProlific producersG proteinsGut microbiota metabolitesBlood-brain barrierL-PheMicrobial metabolitesOrphan GPCRsGut bacteriaColonic motilityInhibitor administrationMicrobiota metabolitesIntestinal microbiotaSmall moleculesDietary histidineBacteriaPhysiologyMicrobiota metabolomeMetabolitesGPR97Orthogonal approachGPCRs
2016
Linking 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 phenotypeMetabolomicsMerging chemical ecology with bacterial genome mining for secondary metabolite discovery
Vizcaino MI, Guo X, Crawford JM. Merging chemical ecology with bacterial genome mining for secondary metabolite discovery. Journal Of Industrial Microbiology & Biotechnology 2014, 41: 285-299. PMID: 24127069, PMCID: PMC3946945, DOI: 10.1007/s10295-013-1356-5.Peer-Reviewed Original ResearchConceptsBacterial genome miningOrphan biosynthetic pathwaysGenome miningChemical ecologyBiosynthetic pathwayBacterial secondary metabolismBiosynthetic gene clusterSecondary metabolic pathwaysSecondary metabolite discoveryLaboratory cultivation conditionsBioactive secondary metabolitesHost-bacteria interactionsMicrobial chemicalSymbiotic lifestylePhotorhabdus bacteriaSecondary metabolismGene clusterMutualistic relationshipSmall moleculesPhenotypic variationEcological nichesDiverse natural productsNatural productsPhysiological attributesSymbiotic system
2010
Exploiting a Global Regulator for Small Molecule Discovery in Photorhabdus luminescens
Kontnik R, Crawford JM, Clardy J. Exploiting a Global Regulator for Small Molecule Discovery in Photorhabdus luminescens. ACS Chemical Biology 2010, 5: 659-665. PMID: 20524642, PMCID: PMC2912427, DOI: 10.1021/cb100117k.Peer-Reviewed Original ResearchConceptsGlobal transcriptional regulatorSmall moleculesSecondary metabolite productionGenes/lociTight regulatory controlUseful biological probesSmall molecule discoverySuch small moleculesGlobal regulatorBacterial genomesFunctional diversityInsect larvaeTranscriptional regulatorsTranscriptional repressorComplex symbiosisNematode wormsMetabolite productionMolecule discoveryPhotorhabdusMutantsDramatic upregulationSymbiosisRegulatory controlRemarkable rangeRegulatorRegulating Alternative Lifestyles in Entomopathogenic Bacteria
Crawford JM, Kontnik R, Clardy J. Regulating Alternative Lifestyles in Entomopathogenic Bacteria. Current Biology 2010, 20: 69-74. PMID: 20022247, PMCID: PMC2821981, DOI: 10.1016/j.cub.2009.10.059.Peer-Reviewed Original ResearchConceptsAntibiotic productionMetabolic shiftNematode digestive tractBacterial proton motive forceBacterial metabolic regulationProton motive forceGenus PhotorhabdusTransporter PutPEntomopathogenic bacteriaInsect larvaeSmall moleculesInsecticidal toxinsNematode hostsInsect hemolymphBacterial pathwaysXenorhabdus nematophilaFungal competitorsDigestive tractL-prolineMetabolic regulationMotive forceHost environmentPhotorhabdusTT01Bacteria