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 ResearchCommensal 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 decarboxylaseLACC1Cross-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 small molecule metabolism at the host–microorganism interface
Gatsios A, Kim CS, Crawford JM. Escherichia coli small molecule metabolism at the host–microorganism interface. Nature Chemical Biology 2021, 17: 1016-1026. PMID: 34552219, PMCID: PMC8675634, DOI: 10.1038/s41589-021-00807-5.Peer-Reviewed Original ResearchConceptsSmall molecule metabolismE. coliHost-bacteria interfaceModel organismsHost-bacterial interactionsChemical arsenalMolecule metabolismEscherichia coliHuman microbiotaColiSmall molecule chemistryMetabolismCommon componentSignalingOrganismsBiologyDisease modulationCommensalEscherichiaHostPathogenic roleRoleMicrobiotaMembersEscherichia 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 structuresMetabolitesLociProteinSpectroscopyMolecules 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
Sulfamethoxazole 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 coliSymptomsIBDStructure 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 cultureResiduesPathwayCleavageCellsStrandsGutDimeric Stilbene Antibiotics Target the Bacterial Cell Wall in Drug-Resistant Gram-Positive Pathogens
Goddard TN, Patel J, Park HB, Crawford JM. Dimeric Stilbene Antibiotics Target the Bacterial Cell Wall in Drug-Resistant Gram-Positive Pathogens. Biochemistry 2020, 59: 1966-1971. PMID: 32410442, PMCID: PMC10578317, DOI: 10.1021/acs.biochem.0c00213.Peer-Reviewed Original ResearchConceptsChemical complementation studiesBacterial cell wallMass spectrometry analysisLipid IILead compoundsMultidrug-resistant Gram-positive pathogensStilbene dimersCell wall precursorsSpectrometry analysisDrug-Resistant GramNew antimicrobial agentsGram-positive pathogensDimersNonlethal exposureAntibiotic targetsPositive pathogensDietary plantsAction studiesAntibiotic resistanceMode of actionAntimicrobial agentsLead dimerWall precursorsMonomersStrong activityA DNA Repair Inhibitor Isolated from an Ecuadorian Fungal Endophyte Exhibits Synthetic Lethality in PTEN-Deficient Glioblastoma
Adaku N, Park HB, Spakowicz DJ, Tiwari MK, Strobel SA, Crawford JM, Rogers FA. A DNA Repair Inhibitor Isolated from an Ecuadorian Fungal Endophyte Exhibits Synthetic Lethality in PTEN-Deficient Glioblastoma. Journal Of Natural Products 2020, 83: 1899-1908. PMID: 32407116, DOI: 10.1021/acs.jnatprod.0c00012.Peer-Reviewed Original ResearchConceptsPTEN-deficient glioblastoma cellsPTEN-deficient cancersTumor suppressor PTENImportant molecular toolPTEN-deficient glioblastomaInhibitor of DNAHuman cancer developmentDNA repair inhibitorsFungal endophytesBreak repairGenomic levelSuppressor PTENMolecular toolsEndophytic fungiSynthetic lethalityPTEN deficiencyGlioblastoma cellsRepair inhibitorsCancer developmentPTEN lossCurrent cancer treatmentsLarger patient populationTherapeutic leadsMedicinal plantsNew therapeutic leadsCellular 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
An Ugi-like Biosynthetic Pathway Encodes Bombesin Receptor Subtype‑3 Agonists
Oh J, Kim NY, Chen H, Palm NW, Crawford JM. An Ugi-like Biosynthetic Pathway Encodes Bombesin Receptor Subtype‑3 Agonists. Journal Of The American Chemical Society 2019, 141: 16271-16278. PMID: 31537063, DOI: 10.1021/jacs.9b04183.Peer-Reviewed Original ResearchA 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
Model Colibactins Exhibit Human Cell Genotoxicity in the Absence of Host Bacteria
Shine EE, Xue M, Patel JR, Healy AR, Surovtseva YV, Herzon SB, Crawford JM. Model Colibactins Exhibit Human Cell Genotoxicity in the Absence of Host Bacteria. ACS Chemical Biology 2018, 13: 3286-3293. PMID: 30403848, PMCID: PMC7001666, DOI: 10.1021/acschembio.8b00714.Peer-Reviewed Original ResearchConceptsHost bacteriaGenotoxic secondary metabolitesDNA double-strand breaksDNA interstrandSpecific protein domainsWild-type pathwayDouble-strand breaksFull molecular mechanismsCell culturesFamily of metabolitesHuman cell linesProtein domainsPresence of membranesModule skippingCellular phenotypesExtracellular supplementationNative pathwaysHuman cell culturesMolecular mechanismsSecondary metabolitesHuman cellsColibactinEfficient DNA interstrandObserved modulesPhenotypeMicrobiota-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 Research
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