2020
Bacterial 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 ResearchMeSH KeywordsAnimalsAnti-Bacterial AgentsAutoimmunityBiotransformationImmunologic FactorsMicePhotorhabdusResorcinolsStilbenesConceptsMethicillin-resistant Staphylococcus aureusVancomycin-resistant Enterococcus faecalisColitis mouse modelInflammatory bowel diseaseInflammatory bacteriaBowel diseaseAtopic dermatitisDietary stilbenesMouse modelDrug metabolismTapinarofStaphylococcus aureusEnterococcus faecalisMetabolism productsDisease symptomsPsoriasisDermatitisImmunomodulatorsSymptomsNrf2Disease
2019
Characterization of a Hybrid Nonribosomal Peptide–Carbohydrate Biosynthetic Pathway in Photorhabdus luminescens
Perez CE, Crawford JM. Characterization of a Hybrid Nonribosomal Peptide–Carbohydrate Biosynthetic Pathway in Photorhabdus luminescens. Biochemistry 2019, 58: 1131-1140. PMID: 30694662, DOI: 10.1021/acs.biochem.8b01120.Peer-Reviewed Original ResearchConceptsHypothetical proteinsBiosynthetic pathwayNRPS machineryHybrid nonribosomal peptide synthetaseBacterial biosynthetic pathwaysStable isotope labelingNonribosomal peptide synthetaseProtein mass spectrometryEntomopathogen PhotorhabdusFascinating chemistryOrphan pathwaysCharacterization of oligosaccharidesAcetyl-glucosamine moietyProduction of metabolitesGenomic islandsGlycoamino acidsNovel chemistryGene clusterHeterologous expressionProtein biochemistryPeptide synthetaseBiological functionsGenome sequencingMass spectrometryIsotope labeling
2018
Functional Characterization of a Condensation Domain That Links Nonribosomal Peptide and Pteridine Biosynthetic Machineries in Photorhabdus luminescens
Perez CE, Park HB, Crawford JM. Functional Characterization of a Condensation Domain That Links Nonribosomal Peptide and Pteridine Biosynthetic Machineries in Photorhabdus luminescens. Biochemistry 2018, 57: 354-361. PMID: 29111689, DOI: 10.1021/acs.biochem.7b00863.Peer-Reviewed Original ResearchConceptsNonribosomal peptide synthetasesCondensation domainMetabolic pathwaysSecondary metabolite biosynthesisSpecialized metabolic pathwaysBiosynthetic gene clusterNRPS condensation domainDistinct enzymatic systemsImportant small moleculesSecondary metabolite analysisCitric acid cycleMetabolite biosynthesisFunctional diversityGene clusterBiosynthetic machineryCellular redoxPeptide synthetasesNonribosomal peptidesBiosynthetic systemsQuorum sensingFunctional characterizationSolution studiesGenetic lociNatural productsBiochemical level
2017
Genome mining unearths a hybrid nonribosomal peptide synthetase-like-pteridine synthase biosynthetic gene cluster
Park HB, Perez CE, Barber KW, Rinehart J, Crawford JM. Genome mining unearths a hybrid nonribosomal peptide synthetase-like-pteridine synthase biosynthetic gene cluster. ELife 2017, 6: e25229. PMID: 28431213, PMCID: PMC5384830, DOI: 10.7554/elife.25229.Peer-Reviewed Original ResearchConceptsBiosynthetic gene clusterNonribosomal peptide synthetaseGene clusterPeptide synthetaseGenome synteny analysisHybrid nonribosomal peptide synthetaseSecondary metabolic enzymesQuantitative proteomic analysisExtensive gene deletionsRedox-active cofactorsSynteny analysisMutualistic roleGenome miningBiosynthetic machineryPhenotypic variationBiosynthetic potentialNonribosomal peptidesProteomic analysisQuorum sensingGenetic lociMetabolic enzymesAcyl side chainPhenotypic variantsGene deletionDistinct classesStilbene 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 assays
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
Lumiquinone A, an α‑Aminomalonate-Derived Aminobenzoquinone from Photorhabdus luminescens
Park HB, Crawford JM. Lumiquinone A, an α‑Aminomalonate-Derived Aminobenzoquinone from Photorhabdus luminescens. Journal Of Natural Products 2015, 78: 1437-1441. PMID: 25988621, PMCID: PMC5055755, DOI: 10.1021/np500974f.Peer-Reviewed Original Research
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 productsMerging 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
2012
A Single Promoter Inversion Switches Photorhabdus Between Pathogenic and Mutualistic States
Somvanshi VS, Sloup RE, Crawford JM, Martin AR, Heidt AJ, Kim KS, Clardy J, Ciche TA. A Single Promoter Inversion Switches Photorhabdus Between Pathogenic and Mutualistic States. Science 2012, 337: 88-93. PMID: 22767929, PMCID: PMC4006969, DOI: 10.1126/science.1216641.Peer-Reviewed Original ResearchConceptsNematode intestinePromoter inversionVariable life historiesM-form cellsInsect infectionHost nematodesLife historyMicrobial populationsSecondary metabolitesAntibiotic toleranceIndividual cellsNematodesPhotorhabdusM formJuvenile offspringCellsPathogenic variantsFirst cellsDistinct formsMutualistsMutualismVariantsInsectsAvirulenceSmall cell variantSmall molecule perimeter defense in entomopathogenic bacteria
Crawford JM, Portmann C, Zhang X, Roeffaers MB, Clardy J. Small molecule perimeter defense in entomopathogenic bacteria. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 10821-10826. PMID: 22711807, PMCID: PMC3390839, DOI: 10.1073/pnas.1201160109.Peer-Reviewed Original ResearchConceptsBacterial cell surfaceConfocal fluorescence microscopyCell surfacePhysical associationHuman pathogen Vibrio choleraeInsect innate immune systemBiochemical assaysInnate immune systemPathogen Vibrio choleraeFluorescence microscopyPrecursor-directed biosynthesisE. coli cellsInsect pathogensPathway mutantsEntomopathogenic bacteriaHeterologous expressionXenorhabdus nematophilaColi cellsEscherichia coliVibrio choleraeClass of moleculesBioorthogonal probesEffective inhibitor concentrationBiosynthesisHost defense
2011
Dihydrophenylalanine: A Prephenate-Derived Photorhabdus luminescens Antibiotic and Intermediate in Dihydrostilbene Biosynthesis
Crawford JM, Mahlstedt SA, Malcolmson SJ, Clardy J, Walsh CT. Dihydrophenylalanine: A Prephenate-Derived Photorhabdus luminescens Antibiotic and Intermediate in Dihydrostilbene Biosynthesis. Cell Chemical Biology 2011, 18: 1102-1112. PMID: 21944749, PMCID: PMC3183431, DOI: 10.1016/j.chembiol.2011.07.009.Peer-Reviewed Original Research
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