2024
A Divergent Synthesis of Numerous Pyrroloiminoquinone Alkaloids Identifies Promising Antiprotozoal Agents
Barnes G, Magann N, Perrotta D, Hörmann F, Fernandez S, Vydyam P, Choi J, Prudhomme J, Neal A, Le Roch K, Mamoun C, Vanderwal C. A Divergent Synthesis of Numerous Pyrroloiminoquinone Alkaloids Identifies Promising Antiprotozoal Agents. Journal Of The American Chemical Society 2024, 146: 29883-29894. PMID: 39412402, PMCID: PMC11528414, DOI: 10.1021/jacs.4c11897.Peer-Reviewed Original ResearchNatural productsLarock indole synthesisAlkaloid natural productsAmine nucleophilesDivergent synthesisIndole synthesisPyrrolic nitrogenMethoxy groupLead compoundsDrug discoveryCompoundsStructural analogsPlasmodium falciparum</i>SynthesisPyrroloiminoquinoneHuman cytotoxicityMalaria parasitesNucleophilesPyrroleAntiprotozoal agentsAminesMammalian cellsIntermediateA kalihinol analog disrupts apicoplast function and vesicular trafficking in P. falciparum malaria
Chahine Z, Abel S, Hollin T, Barnes G, Chung J, Daub M, Renard I, Choi J, Vydyam P, Pal A, Alba-Argomaniz M, Banks C, Kirkwood J, Saraf A, Camino I, Castaneda P, Cuevas M, De Mercado-Arnanz J, Fernandez-Alvaro E, Garcia-Perez A, Ibarz N, Viera-Morilla S, Prudhomme J, Joyner C, Bei A, Florens L, Ben Mamoun C, Vanderwal C, Le Roch K. A kalihinol analog disrupts apicoplast function and vesicular trafficking in P. falciparum malaria. Science 2024, 385: eadm7966. PMID: 39325875, DOI: 10.1126/science.adm7966.Peer-Reviewed Original ResearchConceptsP. falciparum malariaHumanized mouse modelPlasmodium falciparum</i> strainsIn vivo studiesParasite apicoplastDrug sensitivityTherapeutic profileVesicular traffickingGenomic analysisLipid biogenesisSecretory machineryAsexual replicationGenetic analysisReduced susceptibilityCellular traffickingApicoplast functionStrong efficacyMED6Sexual differentiationHemolytic activityDrug pipelineApicoplastKalihinolTraffickingMalariaInsights into the evolution, virulence and speciation of Babesia MO1 and Babesia divergens through multiomics analyses
Singh P, Vydyam P, Fang T, Estrada K, Gonzalez L, Grande R, Kumar M, Chakravarty S, Berry V, Ranwez V, Carcy B, Depoix D, Sánchez S, Cornillot E, Abel S, Ciampossin L, Lenz T, Harb O, Sanchez-Flores A, Montero E, Le Roch K, Lonardi S, Mamoun C. Insights into the evolution, virulence and speciation of Babesia MO1 and Babesia divergens through multiomics analyses. Emerging Microbes & Infections 2024, 13: 2386136. PMID: 39148308, PMCID: PMC11370697, DOI: 10.1080/22221751.2024.2386136.Peer-Reviewed Original ResearchLeveraging genomic informationHuman babesiosisTick-borne diseasesDiseases of significanceCases of human babesiosisGenomic divergenceGenome sequenceGenomic informationMultigene familyGene functionBabesia divergensMammalian hostsAnimal healthMultiomics analysisZoonotic pathogensBabesiosisProtozoan parasitesVirulent strainsPathogensVertebrate hostsEnvironmental changesVirulenceReplication rateAntiparasitic drugsParasitesIn vitro efficacy of next-generation dihydrotriazines and biguanides against babesiosis and malaria parasites
Vydyam P, Chand M, Gihaz S, Renard I, Heffernan G, Jacobus L, Jacobus D, Saionz K, Shah R, Shieh H, Terpinski J, Zhao W, Cornillot E, Mamoun C. In vitro efficacy of next-generation dihydrotriazines and biguanides against babesiosis and malaria parasites. Antimicrobial Agents And Chemotherapy 2024, 68: e00423-24. PMID: 39136469, PMCID: PMC11373198, DOI: 10.1128/aac.00423-24.Peer-Reviewed Original ResearchTherapeutic indexPlasmodium falciparum</i>Effective therapeutic strategyCausative agent of babesiosisIn vitro efficacyAntiparasitic drugsProtozoan parasitesMalaria parasitesIntraerythrocytic protozoan parasiteTherapeutic strategiesFolate pathwayBroad-spectrum antiparasitic drugStrain HB3Babesia divergensMalariaBabesia duncaniAnimal healthAntifolatesDrugWidespread resistanceCausative agentBiguanideBabesiaBabesiosisBiosynthesis of purinesA set of diagnostic tests for detection of active Babesia duncani infection
Chand M, Vydyam P, Pal A, Thekkiniath J, Darif D, Li Z, Choi J, Magni R, Luchini A, Tonnetti L, Horn E, Tufts D, Ben Mamoun C. A set of diagnostic tests for detection of active Babesia duncani infection. International Journal Of Infectious Diseases 2024, 147: 107178. PMID: 39025200, DOI: 10.1016/j.ijid.2024.107178.Peer-Reviewed Original ResearchB. microtiB. duncaniBlood samplesLife-threatening infectionsAntigen capture assayTick-borne diseasesFatal tick-borne diseaseP. falciparumBabesia genusScreening of blood samplesBabesia speciesB. divergensActive infectionAccurate diagnosisEffective disease managementPoint-of-care testingDiagnostic testsReservoir hostsBabesiaInfectionHuman babesiosisIntraerythrocytic parasitesImmunodominant antigensMolecular assaysCapture assayVitamin B5 metabolism is essential for vacuolar and mitochondrial functions and drug detoxification in fungi
Choi J, Gihaz S, Munshi M, Singh P, Vydyam P, Hamel P, Adams E, Sun X, Khalimonchuk O, Fuller K, Ben Mamoun C. Vitamin B5 metabolism is essential for vacuolar and mitochondrial functions and drug detoxification in fungi. Communications Biology 2024, 7: 894. PMID: 39043829, PMCID: PMC11266677, DOI: 10.1038/s42003-024-06595-7.Peer-Reviewed Original ResearchConceptsSusceptibility of fungiRegulation of genesMetabolism of fatty acidsVacuolar morphologySaccharomyces cerevisiaeAcetyl-CoAEukaryotic pathogensGenetic evidenceGenetic regulationCellular processesAntifungal drugsCo-enzyme ADrug detoxificationAntifungal therapyDrug-resistant strainsFungal infectionsMitochondrial functionFungiAmino acidsAR-12Vitamin B5Synthase activityPathwayExcellent targetGlobal health threatEffectiveness of Two New Endochin-like Quinolones, ELQ-596 and ELQ-650, in Experimental Mouse Models of Human Babesiosis
Vydyam P, Chand M, Pou S, Winter R, Liebman K, Nilsen A, Doggett J, Riscoe M, Mamoun C. Effectiveness of Two New Endochin-like Quinolones, ELQ-596 and ELQ-650, in Experimental Mouse Models of Human Babesiosis. ACS Infectious Diseases 2024, 10: 1405-1413. PMID: 38563132, PMCID: PMC11127568, DOI: 10.1021/acsinfecdis.4c00143.Peer-Reviewed Original ResearchConceptsRadical cureEndochin-like quinolonesAgent of human malariaLethal infection modelTreatment of human babesiosisLow toxicity profileExperimental mouse modelImmunocompetent miceImmunocompromised miceFavorable pharmacological propertiesHuman malariaToxicity profileChronic modelHuman babesiosisAnimal modelsInfection modelPharmacological limitationsActivity in vitroPharmacological propertiesReduce infectionQuinolonesMiceMitochondrial electron transport chainFavorable physicochemical propertiesMonotherapyResponse to the Letter by Liu and Colleagues
Mamoun C, Vydyam P. Response to the Letter by Liu and Colleagues. The Journal Of Infectious Diseases 2024, 229: 1601-1601. PMID: 38471083, DOI: 10.1093/infdis/jiae084.Peer-Reviewed Original ResearchTafenoquine-Atovaquone Combination Achieves Radical Cure and Confers Sterile Immunity in Experimental Models of Human Babesiosis
Vydyam P, Pal A, Renard I, Chand M, Kumari V, Gennaro J, Mamoun C. Tafenoquine-Atovaquone Combination Achieves Radical Cure and Confers Sterile Immunity in Experimental Models of Human Babesiosis. The Journal Of Infectious Diseases 2024, 229: 161-172. PMID: 38169301, PMCID: PMC10786256, DOI: 10.1093/infdis/jiad315.Peer-Reviewed Original Research
2023
Babesia BdFE1 esterase is required for the anti-parasitic activity of the ACE inhibitor fosinopril
Vydyam P, Choi J, Gihaz S, Chand M, Gewirtz M, Thekkiniath J, Lonardi S, Gennaro J, Mamoun C. Babesia BdFE1 esterase is required for the anti-parasitic activity of the ACE inhibitor fosinopril. Journal Of Biological Chemistry 2023, 299: 105313. PMID: 37797695, PMCID: PMC10663679, DOI: 10.1016/j.jbc.2023.105313.Peer-Reviewed Original ResearchConceptsAngiotensin converting enzyme (ACE) inhibitorsACE inhibitor fosinoprilTick-borne illnessConverting Enzyme InhibitorsVector-borne parasitic diseaseClass of drugsNovel drug targetsApicomplexan parasitesMass spectrometry analysisAnti-parasitic activityHeart failureSafe therapyParasite developmentDrug targetsEnzyme inhibitorsParasitic diseasesDrug resistanceTreatment of diseasesHuman babesiosisBabesia parasitesIntraerythrocytic parasitesSuch diseasesDiseaseSpectrometry analysisParasitesUncovering the role of Rad51 in homologous recombination-mediated antigenic diversification in the human malaria parasite Plasmodium falciparum
Vydyam P, Roy N, Bhattacharyya M. Uncovering the role of Rad51 in homologous recombination-mediated antigenic diversification in the human malaria parasite Plasmodium falciparum. Frontiers In Molecular Biosciences 2023, 10: 1223682. PMID: 37593128, PMCID: PMC10427863, DOI: 10.3389/fmolb.2023.1223682.Peer-Reviewed Original ResearchRecombination eventsHuman malaria parasite Plasmodium falciparumAntigenic variationMalaria parasite Plasmodium falciparumRole of RAD51Generation of diversityWhole genome sequencing approachParasite Plasmodium falciparumHuman malaria parasiteMultigene familyGene diversificationRecombinase functionGene repertoireHomologous recombinationGenomic rearrangementsSequencing approachSequence rearrangementsKey molecular factorsParasite linesMolecular determinantsAntigenic diversificationMalaria parasitesChronicity of infectionMolecular factorsImmune evasion mechanismsBabesia duncani multi-omics identifies virulence factors and drug targets
Singh P, Lonardi S, Liang Q, Vydyam P, Khabirova E, Fang T, Gihaz S, Thekkiniath J, Munshi M, Abel S, Ciampossin L, Batugedara G, Gupta M, Lu X, Lenz T, Chakravarty S, Cornillot E, Hu Y, Ma W, Gonzalez L, Sánchez S, Estrada K, Sánchez-Flores A, Montero E, Harb O, Le Roch K, Mamoun C. Babesia duncani multi-omics identifies virulence factors and drug targets. Nature Microbiology 2023, 8: 845-859. PMID: 37055610, PMCID: PMC10159843, DOI: 10.1038/s41564-023-01360-8.Peer-Reviewed Original ResearchConceptsDrug targetsVirulence factorsCandidate virulence factorsRNA-seq dataIntraerythrocytic life cycleAttractive drug targetB. duncaniNuclear genomeGenome annotationApicomplexan parasitesApicomplexan pathogensEpigenetic profilesEpigenetic analysisParasite metabolismMalaria-like diseaseHuman erythrocytesLife cycle stagesBabesia speciesGenomeMetabolic requirementsCycle stagesLife cycleBiologySmall moleculesPotent inhibitorFront Cover: A Chimeric Peptide Inhibits Red Blood Cell Invasion by Plasmodium falciparum with Hundredfold Increased Efficacy (ChemBioChem 7/2023)**
Mannuthodikayil J, Sinha S, Singh S, Biswas A, Ali I, Mashurabad P, Tabassum W, Vydyam P, Bhattacharyya M, Mandal K. Front Cover: A Chimeric Peptide Inhibits Red Blood Cell Invasion by Plasmodium falciparum with Hundredfold Increased Efficacy (ChemBioChem 7/2023)**. ChemBioChem 2023, 24 DOI: 10.1002/cbic.202300043.Peer-Reviewed Original Research
2022
Babesia duncani as a Model Organism to Study the Development, Virulence, and Drug Susceptibility of Intraerythrocytic Parasites In Vitro and In Vivo
Pal AC, Renard I, Singh P, Vydyam P, Chiu JE, Pou S, Winter RW, Dodean R, Frueh L, Nilsen AC, Riscoe MK, Doggett JS, Mamoun C. Babesia duncani as a Model Organism to Study the Development, Virulence, and Drug Susceptibility of Intraerythrocytic Parasites In Vitro and In Vivo. The Journal Of Infectious Diseases 2022, 226: 1267-1275. PMID: 35512141, PMCID: PMC10233494, DOI: 10.1093/infdis/jiac181.Peer-Reviewed Original ResearchConceptsLethal infectionC3H/HeJ miceMalaria-like illnessB. duncaniMouse genetic backgroundSurvival outcomesHeJ miceSevere diseaseBabesia duncaniMouse modelDifferent mouse genetic backgroundsDrug susceptibilityBabesia microtiHuman babesiosisIntraerythrocytic parasitesUnique pathogenParasite loadMiceSpecies of BabesiaApicomplexa phylumInfectionBabesia parasitesFree merozoitesHuman erythrocytesGenetic background
2021
Effective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection
Chiu JE, Renard I, Pal AC, Singh P, Vydyam P, Thekkiniath J, Kumar M, Gihaz S, Pou S, Winter RW, Dodean R, Frueh L, Nilsen AC, Riscoe MK, Doggett JS, Mamoun C. Effective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection. Antimicrobial Agents And Chemotherapy 2021, 65: 10.1128/aac.00662-21. PMID: 34152821, PMCID: PMC8370247, DOI: 10.1128/aac.00662-21.Peer-Reviewed Original ResearchConceptsEndochin-like quinolonesLethal infectionBlood-borne diseasesBlood-borne pathogensEffective therapyRelated apicomplexan parasitesExperimental therapiesLow doseMouse modelInfectious agentsHuman infectionsInfectionClinical candidatesStrong efficacyB. microtiExcellent safetyMode of actionTherapyErythrocytic developmentAtovaquoneEfficacyApicomplexan parasitesSafetyStructure-activity relationshipsParasitemiaEvidence for SARS-CoV-2 Spike Protein in the Urine of COVID-19 Patients
George S, Pal AC, Gagnon J, Timalsina S, Singh P, Vydyam P, Munshi M, Chiu JE, Renard I, Harden CA, Ott IM, Watkins AE, Vogels CBF, Lu P, Tokuyama M, Venkataraman A, Casanovas-Massana A, Wyllie AL, Rao V, Campbell M, Farhadian SF, Grubaugh ND, Dela Cruz CS, Ko AI, Perez A, Akaho EH, Moledina DG, Testani J, John AR, Ledizet M, Mamoun CB, Team A. Evidence for SARS-CoV-2 Spike Protein in the Urine of COVID-19 Patients. Kidney360 2021, 2: 924-936. PMID: 35373072, PMCID: PMC8791366, DOI: 10.34067/kid.0002172021.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 spike proteinSARS-CoV-2Spike proteinUrine samplesSARS-CoV-2 infectionYale-New Haven HospitalCOVID-19 patientsAntigen capture assayDetectable viral RNANew Haven HospitalPositive PCR resultsPossible long-term consequencesSpike S1 proteinNP PCRChildren's HospitalNasopharyngeal swabsSARS-CoV-2 spike S1 proteinRenal abnormalitiesLong-term effectsCystatin CLong-term consequencesHospitalUrineViral RNAAlbuminuria
2019
Benzimidazolinone-Free Peptide o‑Aminoanilides for Chemical Protein Synthesis
Mannuthodikayil J, Singh S, Biswas A, Kar A, Tabassum W, Vydyam P, Bhattacharyya M, Mandal K. Benzimidazolinone-Free Peptide o‑Aminoanilides for Chemical Protein Synthesis. Organic Letters 2019, 21: 9040-9044. PMID: 31663760, DOI: 10.1021/acs.orglett.9b03440.Peer-Reviewed Original ResearchConceptsPeptide synthesisSolid-phase peptide synthesisChemical protein synthesisPhase peptide synthesisTotal chemical synthesisSerious side reactionsPeptide thioestersChemical synthesisEfficient synthesisSide reactionsDiaminobenzoic acidO-aminoanilidesSynthesisThioestersAminesBocFormationCarbamateHereinReactionOptional attachmentSolubility tagAcidPeptidesC-terminusA small-molecule inhibitor of the DNA recombinase Rad51 from Plasmodium falciparum synergizes with the antimalarial drugs artemisinin and chloroquine
Vydyam P, Dutta D, Sutram N, Bhattacharyya S, Bhattacharyya M. A small-molecule inhibitor of the DNA recombinase Rad51 from Plasmodium falciparum synergizes with the antimalarial drugs artemisinin and chloroquine. Journal Of Biological Chemistry 2019, 294: 8171-8183. PMID: 30936202, PMCID: PMC6527153, DOI: 10.1074/jbc.ra118.005009.Peer-Reviewed Original ResearchConceptsMultidrug-resistant parasitesAnti-parasitic activitySmall molecule inhibitorsMalaria drugsAntimalarial drugsChloroquinePotential drug targetsAntigenic diversityAntimalarial activityCell linesParasitic DNADNA double-strand breaksSpecific inhibitorDrug targetsDrugsInhibitorsParasitesPfRad51DNA-damaging agentsHigh affinityScreening approachFindingsHomologous recombinationMammalian cell linesActivity
2015
Identification of Plasmodium falciparum DNA Repair Protein Mre11 with an Evolutionarily Conserved Nuclease Function.
Badugu SB, Nabi SA, Vaidyam P, Laskar S, Bhattacharyya S, Bhattacharyya MK. Identification of Plasmodium falciparum DNA Repair Protein Mre11 with an Evolutionarily Conserved Nuclease Function. PLoS One 2015, 10: e0125358. PMID: 25938776, DOI: 10.1371/journal.pone.0125358.Peer-Reviewed Original Research