2022
Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites
Cao Y, Oh J, Xue M, Huh WJ, Wang J, Gonzalez-Hernandez JA, Rice TA, Martin AL, Song D, Crawford JM, Herzon SB, Palm NW. Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites. Science 2022, 378: eabm3233. PMID: 36302024, PMCID: PMC9993714, DOI: 10.1126/science.abm3233.Peer-Reviewed Original ResearchConceptsColorectal cancerInflammatory bowel disease patientsBowel disease patientsInflammatory bowel diseaseIndigenous gut microbesBowel diseaseDisease patientsCommensal microbiotaDNA damageColon tumorigenesisElicit DNA damageGut microbesGenotoxic metabolitesGut commensalsMorganella morganiiPatientsGenotoxic chemicalsDiseaseMicrobiotaMetabolitesGenotoxicityCancerMiceFull spectrumDamageN‐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.MeningitisLACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages
Wei Z, Oh J, Flavell RA, Crawford JM. LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages. Nature 2022, 609: 348-353. PMID: 35978195, PMCID: PMC9813773, DOI: 10.1038/s41586-022-05111-3.Peer-Reviewed Original ResearchConceptsInflammatory bowel diseaseWild-type activityCentral regulatory roleMammalian immune systemBone marrow-derived macrophagesInflammatory macrophagesBiochemical functionsBowel diseaseSignaling outcomesMarrow-derived macrophagesPattern recognition receptorsInflammatory diseasesBiochemical roleRegulatory roleMechanistic connectionUnidentified pathwaySalmonella enterica TyphimuriumNitric oxide synthaseRecognition receptorsHost damageHuman inflammatory diseasesMultiple inflammatory diseasesEnterica TyphimuriumOrnithine decarboxylaseLACC1RNA m6A demethylase ALKBH5 regulates the development of γδ T cells
Ding C, Xu H, Yu Z, Roulis M, Qu R, Zhou J, Oh J, Crawford J, Gao Y, Jackson R, Sefik E, Li S, Wei Z, Skadow M, Yin Z, Ouyang X, Wang L, Zou Q, Su B, Hu W, Flavell RA, Li HB. RNA m6A demethylase ALKBH5 regulates the development of γδ T cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2203318119. PMID: 35939687, PMCID: PMC9388086, DOI: 10.1073/pnas.2203318119.Peer-Reviewed Original ResearchConceptsDemethylase ALKBH5Messenger RNAΓδ T cellsΓδ T cell biologyCommon posttranscriptional modificationΓδ T cell developmentT cell biologyT cell developmentCell precursorsT cell precursorsMammalian cellsRNA modificationsPosttranscriptional modificationsTissue homeostasisCell biologyT cellsTarget genesCheckpoint roleCell developmentM6A demethylase ALKBH5ALKBH5Γδ T-cell originΓδ T cell repertoireCell populationsEarly developmentFossil biomolecules reveal an avian metabolism in the ancestral dinosaur
Wiemann J, Menéndez I, Crawford JM, Fabbri M, Gauthier JA, Hull PM, Norell MA, Briggs DEG. Fossil biomolecules reveal an avian metabolism in the ancestral dinosaur. Nature 2022, 606: 522-526. PMID: 35614213, DOI: 10.1038/s41586-022-04770-6.Peer-Reviewed Original ResearchConceptsHigh metabolic rateCretaceous mass extinctionTerminal Cretaceous mass extinctionLate Cretaceous taxaMetabolic rateCrown mammalsAvian lineagesAncestral stateEcological nichesGiant sauropodsCretaceous taxaMammalsMetabolic abilitiesMetabolic performanceMass extinctionBirdsPhysiological activityEndothermyAvian metabolismCostly adaptationsMetabolismVivo accumulationTheropodsOrnithischiansEctotherms
2020
Making 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 oxytocaInhibitorsGammaproteobacteriaLigasesXenorhabdusPhotorhabdusBiosynthesisSpeciesSulfamethoxazole drug stress upregulates antioxidant immunomodulatory metabolites in Escherichia coli
Park HB, Wei Z, Oh J, Xu H, Kim CS, Wang R, Wyche TP, Piizzi G, Flavell RA, Crawford JM. Sulfamethoxazole drug stress upregulates antioxidant immunomodulatory metabolites in Escherichia coli. Nature Microbiology 2020, 5: 1319-1329. PMID: 32719505, PMCID: PMC7581551, DOI: 10.1038/s41564-020-0763-4.Peer-Reviewed Original ResearchConceptsAnti-inflammatory interleukin-10Colitis mouse modelInflammatory bowel diseaseColitis symptomsBowel diseaseInterleukin-10Immunological markersPathogenic roleImmunomodulatory metabolitesImmunomodulatory phenotypeGastrointestinal tractMouse modelImmunological activityPrimary human tissuesDrug stressSubinhibitory levelsHuman tissuesEnvironmental isolatesCertain strainsMetabolic pathwaysMetabolitesPatientsEscherichia coliSymptomsIBDPhylogenetic and physiological signals in metazoan fossil biomolecules
Wiemann J, Crawford JM, Briggs DEG. Phylogenetic and physiological signals in metazoan fossil biomolecules. Science Advances 2020, 6: eaba6883. PMID: 32832604, PMCID: PMC7439315, DOI: 10.1126/sciadv.aba6883.Peer-Reviewed Original ResearchConceptsEvolutionary historyPhylogenetic informationMetazoan relationshipsMolecular signalsAnimal formsRelative abundanceDifferent tissue typesDeep timeLipoxidation productsTissue typesMetazoan fossilsMolecular compositionMolecular heterogeneityProteinBiological signalsFossil organic matterLipidsPowerful toolSugarsAbundanceLipoxidationGlycoxidationFossilsOrganic matterFossilizationStructure 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 cultureResiduesPathwayCleavageCellsStrandsGutCellular 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 modelMetabolitesBacterial Autoimmune Drug Metabolism Transforms an Immunomodulator into Structurally and Functionally Divergent Antibiotics
Park HB, Goddard TN, Oh J, Patel J, Wei Z, Perez CE, Mercado BQ, Wang R, Wyche TP, Piizzi G, Flavell RA, Crawford J. Bacterial Autoimmune Drug Metabolism Transforms an Immunomodulator into Structurally and Functionally Divergent Antibiotics. Angewandte Chemie International Edition 2020, 59: 7871-7880. PMID: 32097515, PMCID: PMC7200298, DOI: 10.1002/anie.201916204.Peer-Reviewed Original ResearchConceptsMethicillin-resistant Staphylococcus aureusVancomycin-resistant Enterococcus faecalisColitis mouse modelInflammatory bowel diseaseInflammatory bacteriaBowel diseaseAtopic dermatitisDietary stilbenesMouse modelDrug metabolismTapinarofStaphylococcus aureusEnterococcus faecalisMetabolism productsDisease symptomsPsoriasisDermatitisImmunomodulatorsSymptomsNrf2Disease
2019
Disruption of mosGILT in Anopheles gambiae impairs ovarian development and Plasmodium infection
Yang J, Schleicher TR, Dong Y, Park HB, Lan J, Cresswell P, Crawford J, Dimopoulos G, Fikrig E. Disruption of mosGILT in Anopheles gambiae impairs ovarian development and Plasmodium infection. Journal Of Experimental Medicine 2019, 217: e20190682. PMID: 31658986, PMCID: PMC7037243, DOI: 10.1084/jem.20190682.Peer-Reviewed Original ResearchConceptsMutant mosquitoesOvarian developmentThioester-containing protein 1Rodent Plasmodium speciesMajor yolk proteinInducible lysosomal thiol reductaseAbility of sporozoitesExpression of vitellogeninLysosomal thiol reductaseAnopheles gambiae mosquitoesPlasmodium infectionMosquito immunityProtein 9Yolk proteinsThiol reductaseVertebrate hostsTraverse cellsMosquito factorsGambiae mosquitoesProtein 1Plasmodium speciesAnophelesMosquitoesMosaic mutationsParasite killingA 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
2018
Microbiota-Regulated Outcomes of Human Cancer Immunotherapy via the PD-1/PD-L1 Axis
Patel J, Crawford JM. Microbiota-Regulated Outcomes of Human Cancer Immunotherapy via the PD-1/PD-L1 Axis. Biochemistry 2018, 57: 901-903. PMID: 29350031, DOI: 10.1021/acs.biochem.7b01249.Peer-Reviewed Original Research
2017
A New Nucleoside Antibiotic Chokes Bacterial RNA Polymerase
Trautman EP, Crawford JM. A New Nucleoside Antibiotic Chokes Bacterial RNA Polymerase. Biochemistry 2017, 56: 4923-4924. PMID: 28885002, DOI: 10.1021/acs.biochem.7b00680.Peer-Reviewed Original ResearchAcyl 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' diseaseAmoebaeProtozoaMacrophagesPathogensStilbene epoxidation and detoxification in a Photorhabdus luminescens-nematode symbiosis
Park HB, Sampathkumar P, Perez CE, Lee JH, Tran J, Bonanno JB, Hallem EA, Almo SC, Crawford JM. Stilbene epoxidation and detoxification in a Photorhabdus luminescens-nematode symbiosis. Journal Of Biological Chemistry 2017, 292: 6680-6694. PMID: 28246174, PMCID: PMC5399116, DOI: 10.1074/jbc.m116.762542.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnti-Infective AgentsBiological ProductsCatalysisChromatography, High Pressure LiquidCrystallography, X-RayDNA Mutational AnalysisEpoxy CompoundsGene DeletionHydrogen BondingHydrophobic and Hydrophilic InteractionsImmunosuppressive AgentsMagnetic Resonance SpectroscopyMolecular ConformationMutationPhotorhabdusProtein FoldingRhabditoideaStereoisomerismStilbenesSymbiosisConceptsFood signalsInsect infection modelFAD-dependent monooxygenasesFAD prosthetic groupOrphan proteinsInsect larvaeMutualistic relationshipEpoxidase geneNematode developmentCellular detoxificationBiological roleProsthetic groupIntracellular detoxificationAnimal infection modelsInfection modelBiochemical analysisChemical degradation studiesStructural viewNematodesDetoxificationNew insightsCompound 1Major componentNew stilbeneRecovery assaysMetabolite exchange between microbiome members produces compounds that influence Drosophila behavior
Fischer C, Trautman EP, Crawford JM, Stabb EV, Handelsman J, Broderick NA. Metabolite exchange between microbiome members produces compounds that influence Drosophila behavior. ELife 2017, 6: e18855. PMID: 28068220, PMCID: PMC5222558, DOI: 10.7554/elife.18855.Peer-Reviewed Original ResearchConceptsMicrobial communitiesContext-dependent fitness benefitsMulti-species microbial communitiesMicrobial community influencesMicrobe-microbe interactionsEgg-laying preferenceInter-species interactionsEgg-laying behaviorHost-microbiome interactionsDistinct volatile profileMicrobiome membersFitness benefitsMetabolite exchangePopulation declineDrosophila behaviorMolecular mechanismsOlfactory receptorsMetabolic derivativesEthanol catabolismAnimal behaviorCurrent understandingMicrobiomeOr42bIndividual membersDrosophila
2016
Pyrazinone protease inhibitor metabolites from Photorhabdus luminescens
Park HB, Crawford JM. Pyrazinone protease inhibitor metabolites from Photorhabdus luminescens. The Journal Of Antibiotics 2016, 69: 616-621. PMID: 27353165, PMCID: PMC5003743, DOI: 10.1038/ja.2016.79.Peer-Reviewed Original ResearchConceptsSpecialized metabolitesNew specialized metabolitesMutualistic associationAmino acid levelsInsect pathogenesisInsect preyGalleria mellonella larvaePhotorhabdus genusP. luminescensPhenotypic variationFamilies HeterorhabditidaeNematode developmentEntomopathogenic bacteriumProtease inhibitory activityFree amino acid levelsRich mediumAmino acidsMellonella larvaePhenotypic variantsMarfey's analysisPhotorhabdusCirculatory fluidCulture extractsMetabolitesHeterorhabditidae
2015
Gut Symbionts from Distinct Hosts Exhibit Genotoxic Activity via Divergent Colibactin Biosynthesis Pathways
Engel P, Vizcaino MI, Crawford JM. Gut Symbionts from Distinct Hosts Exhibit Genotoxic Activity via Divergent Colibactin Biosynthesis Pathways. Applied And Environmental Microbiology 2015, 81: 1502-1512. PMID: 25527542, PMCID: PMC4309719, DOI: 10.1128/aem.03283-14.Peer-Reviewed Original ResearchConceptsNonribosomal peptide synthetaseBiosynthetic pathwayBacterial symbiontsGut symbiontsSecondary metabolitesEukaryotic cellsGenomic islandsBacterial gut symbiontDiverse symbiotic associationsDivergent variantsDNA damagePolyketide synthase pathwayE. coliComparative metabolomic analysisRelated secondary metabolitesPathway-dependent mannerSymbiotic associationGene clusterMicrobial interactionsBiosynthesis pathwayDistinct hostsPeptide synthetaseMammalian gutHoney beesSymbionts