2025
P-788. Exploring β-Lactam Interactions with DacB1: Unraveling Optimal Therapies for Combating Drug-Resistant Mycobacterium tuberculosis
Nantongo M, Nguyen D, Shin E, Bethel C, Taracila M, Dousa K, Kurz S, Nguyen L, Kreiswirth B, Boom W, Bonomo R. P-788. Exploring β-Lactam Interactions with DacB1: Unraveling Optimal Therapies for Combating Drug-Resistant Mycobacterium tuberculosis. Open Forum Infectious Diseases 2025, 12: ofae631.982. PMCID: PMC11778675, DOI: 10.1093/ofid/ofae631.982.Peer-Reviewed Original ResearchMinimum inhibitory concentrationAcyl-enzyme adductOxyanion holeB-lactamB-lactamasePeptidoglycan synthesis pathwayCarbonyl groupHydrophobic interactionsElectrospray ionization mass spectrometryAcyl-enzyme formationB-lactam antibioticsMichaelis-Menten complexC1‐methyl groupProtein motifsPeptidoglycan biosynthesisDrug-resistant Mycobacterium tuberculosisIonization mass spectrometryPeptidoglycan synthesisD-carboxypeptidaseAnalysis of meropenemB-lactamase inhibitorsClinical isolatesBroth microdilutionClinically achievable concentrationsSynthesis pathway
2024
Durlobactam in combination with β-lactams to combat Mycobacterium abscessus
Shin E, Dousa K, Taracila M, Bethel C, Nantongo M, Nguyen D, Akusobi C, Kurz S, Plummer M, Daley C, Holland S, Rubin E, Bulitta J, Boom W, Kreiswirth B, Bonomo R. Durlobactam in combination with β-lactams to combat Mycobacterium abscessus. Antimicrobial Agents And Chemotherapy 2024, 69: e01174-24. PMID: 39714147, PMCID: PMC11823594, DOI: 10.1128/aac.01174-24.Peer-Reviewed Original ResearchSynergistic effects of sulopenem in combination with cefuroxime or durlobactam against Mycobacterium abscessus
Dousa K, Shin E, Kurz S, Plummer M, Nantongo M, Bethel C, Taracila M, Nguyen D, Kreiswith B, Daley C, Remy K, Holland S, Bonomo R. Synergistic effects of sulopenem in combination with cefuroxime or durlobactam against Mycobacterium abscessus. MBio 2024, 15: e00609-24. PMID: 38742824, PMCID: PMC11237399, DOI: 10.1128/mbio.00609-24.Peer-Reviewed Original ResearchConceptsD,D-carboxypeptidaseMinimum inhibitory concentrationB-lactamPenicillin-binding-proteinCell wall synthesisL,D-transpeptidasesResistance to common antibioticsLowest minimum inhibitory concentrationWall synthesisCystic fibrosisD-carboxypeptidaseMass spectrometry analysisB-lactamaseThioester bondRate of treatment failureCell-based assaysMultiple antibioticsB-lactam ringsCommon antibioticsD-transpeptidasesB-lactamase inhibitorsCysteine residuesTime-kill studiesStructural lung diseaseMultidrug-resistant tuberculosisDurlobactam, a Diazabicyclooctane β‑Lactamase Inhibitor, Inhibits BlaC and Peptidoglycan Transpeptidases of Mycobacterium tuberculosis
Nantongo M, Nguyen D, Bethel C, Taracila M, Li Q, Dousa K, Shin E, Kurz S, Nguyen L, Kreiswirth B, Boom W, Plummer M, Bonomo R. Durlobactam, a Diazabicyclooctane β‑Lactamase Inhibitor, Inhibits BlaC and Peptidoglycan Transpeptidases of Mycobacterium tuberculosis. ACS Infectious Diseases 2024, 10: 1767-1779. PMID: 38619138, DOI: 10.1021/acsinfecdis.4c00119.Peer-Reviewed Original ResearchConceptsESI-MSElectrospray ionization mass spectrometryIonization mass spectrometryB-lactamase inhibitorsAcyl-enzyme complexMycobacterial cell wall synthesisMolecular dockingMass spectrometryActive siteInhibit BlaCPeptidoglycan transpeptidaseDiazabicyclooctaneSynthesisAntibiotic susceptibility testingCell wall synthesisInhibition kineticsDrug targetsB-lactamaseDurlobactamSusceptibility testingComplexDockingSpectrometryWall synthesisPeptidoglycan synthesis
2022
1432. Exploring Cell Wall Targets to Overcome Mycobacterium tuberculosis (Mtb): Ceftriaxone (CRO) Inhibits LdtMt2, a Major Peptidoglycan (PG) Synthase
Nguyen D, Redmond S, Dousa K, Bethel C, Taracila M, Li Q, Kurz S, Pavelka M, Papp-Wallace K, Holland S, Kreiswirth B, Boom H, Bonomo R. 1432. Exploring Cell Wall Targets to Overcome Mycobacterium tuberculosis (Mtb): Ceftriaxone (CRO) Inhibits LdtMt2, a Major Peptidoglycan (PG) Synthase. Open Forum Infectious Diseases 2022, 9: ofac492.1261. PMCID: PMC9752925, DOI: 10.1093/ofid/ofac492.1261.Peer-Reviewed Original ResearchDrug-resistant tuberculosisB-lactamaseMTB isolatesDifficult-to-treat infectionsB-lactamase inhibitorsFractional inhibitory concentration indexMultidrug-resistant mycobacteriaIn vitro susceptibilityCystic Fibrosis FoundationBroth microdilution methodPG synthasesElectrospray ionization-mass spectrometryCeftriaxone MICsDR-TBSusceptibility testingImipenemMeropenemTB guidelinesCeftriaxoneB-lactamTreatment strategiesClinical studiesLowered MICClavulanateMicrodilution methodInhibiting Mycobacterium abscessus Cell Wall Synthesis: Using a Novel Diazabicyclooctane β-Lactamase Inhibitor To Augment β-Lactam Action
Dousa K, Nguyen D, Kurz S, Taracila M, Bethel C, Schinabeck W, Kreiswirth B, Brown S, Boom W, Hotchkiss R, Remy K, Jacono F, Daley C, Holland S, Miller A, Bonomo R. Inhibiting Mycobacterium abscessus Cell Wall Synthesis: Using a Novel Diazabicyclooctane β-Lactamase Inhibitor To Augment β-Lactam Action. MBio 2022, 13: e03529-21. PMID: 35073757, PMCID: PMC8787486, DOI: 10.1128/mbio.03529-21.Peer-Reviewed Original ResearchConceptsD-carboxypeptidaseB-lactamB-lactamaseDisrupt cell wall synthesisStable acyl-enzyme complexesCell wall synthesisAcyl-enzyme complexMichaelis-Menten complexB-lactamase inhibitorsWall synthesisPeptidoglycan synthesisStructural lung diseaseTriple drug combinationIsolates to amoxicillinCell-based assaysMycobacterium abscessusMIC rangeImipenemMichaelis constantAcylation rateInhibitor combinationsDurlobactamMultidrug resistanceTherapeutic regimensCystic fibrosis
2020
1642. A Novel β-lactamase Inhibitor (Durlobactam, DUR) and β-Lactams Enhance Susceptibility Against Multidrug-Resistant (MDR) Mycobacterium abscessus (Mab)
Dousa K, Kurz S, Bethel C, Miller A, Bonomo R. 1642. A Novel β-lactamase Inhibitor (Durlobactam, DUR) and β-Lactams Enhance Susceptibility Against Multidrug-Resistant (MDR) Mycobacterium abscessus (Mab). Open Forum Infectious Diseases 2020, 7: s810-s811. PMCID: PMC7777676, DOI: 10.1093/ofid/ofaa439.1822.Peer-Reviewed Original ResearchMinimum inhibitory concentrationB-lactamAmbler class AB-lactamase inhibitorsStructural lung diseaseB-lactam antibioticsImprove treatment outcomesTargeting multiple stepsMiddlebrook 7H9 brothVisible bacterial growthB-lactamaseDurlobactamBlaMabClinical isolatesColony-forming unitsMechanism of actionLung infectionCell wall structureRestore susceptibilityClinical strainsHydrolyzed penicillinsNontuberculous mycobacteriaLung diseaseMAB isolatesTreatment outcomesInsights into the l,d-Transpeptidases and d,d-Carboxypeptidase of Mycobacterium abscessus: Ceftaroline, Imipenem, and Novel Diazabicyclooctane Inhibitors
Dousa K, Kurz S, Taracila M, Bonfield T, Bethel C, Barnes M, Selvaraju S, Abdelhamed A, Kreiswirth B, Boom W, Kasperbauer S, Daley C, Bonomo R. Insights into the l,d-Transpeptidases and d,d-Carboxypeptidase of Mycobacterium abscessus: Ceftaroline, Imipenem, and Novel Diazabicyclooctane Inhibitors. Antimicrobial Agents And Chemotherapy 2020, 64: 10.1128/aac.00098-20. PMID: 32393499, PMCID: PMC7526840, DOI: 10.1128/aac.00098-20.Peer-Reviewed Original ResearchConceptsCeftaroline fosamilB-lactamB-lactamaseNontuberculous mycobacteriaB-lactamase inhibitorsD-carboxypeptidaseB-lactam antibioticsCell wall synthesis proteinsCeftarolineImipenemDiazabicyclooctane inhibitorSteady-state kinetic assaysAvibactamHighest acylation ratesMechanism-based approachGt;100-foldRelebactamSynthesis proteinsD-transpeptidasesKinetic assaysAcylation rateInhibitors
2019
1385. Mechanism-Based, In Vitro Inhibition of Mycobacterium abscessus: Assessing β-Lactam Therapy
Dousa K, Kurz S, Bethel C, Barnes M, Taracilla M, Selvaraju S, Jacobs M, Kreiswirth B, Kasperbauer S, Daley C, Bonomo R. 1385. Mechanism-Based, In Vitro Inhibition of Mycobacterium abscessus: Assessing β-Lactam Therapy. Open Forum Infectious Diseases 2019, 6: s503-s503. PMCID: PMC6809419, DOI: 10.1093/ofid/ofz360.1249.Peer-Reviewed Original ResearchB-lactamaseColony-forming unitsIn vitro susceptibility testingB-lactamase inhibitorsTherapeutically achievable concentrationsMab infectionRescue regimenMiddlebrook 7H9 brothVisible bacterial growthSusceptibility testingClinical isolatesImipenemBlaMabTreated patientsRelebactamAvibactamNontuberculous mycobacteriaB-lactamM. abscessusMAB isolatesTest agentsIn vitro inhibitionMAb complexesMAbMIC
2018
786. Ceftaroline and Avibactam? Is This a Potential Combination for Mycobacterium abscessus Infection?
Dousa K, Kreiswirth B, Kurz S, Bonomo R. 786. Ceftaroline and Avibactam? Is This a Potential Combination for Mycobacterium abscessus Infection? Open Forum Infectious Diseases 2018, 5: s281-s281. PMCID: PMC6254396, DOI: 10.1093/ofid/ofy210.793.Peer-Reviewed Original ResearchB-lactamB-lactamase inhibitorsMycobacterium abscessus infectionB-lactam antibioticsBenefits of combinationB-lactamaseCeftarolineHydrolyzed penicillinsMycobacterium abscessusAvibactamDiazabicyclooctane inhibitorBlaMabMycobacterial infectionMicrodilution methodClinical modelDiazabicyclooctaneInhibitorsInfectionMICInhibited growthNovel combinationCarbapenemsPotential combinationRelebactamMIC90
2015
Kinetic and Structural Characterization of the Interaction of 6‑Methylidene Penem 2 with the β‑Lactamase from Mycobacterium tuberculosis
Hazra S, Kurz S, Wolff K, Nguyen L, Bonomo R, Blanchard J. Kinetic and Structural Characterization of the Interaction of 6‑Methylidene Penem 2 with the β‑Lactamase from Mycobacterium tuberculosis. Biochemistry 2015, 54: 5657-5664. PMID: 26237118, PMCID: PMC4795174, DOI: 10.1021/acs.biochem.5b00698.Peer-Reviewed Original ResearchConceptsB-lactamaseB-lactamPenem 2Inhibit BlaCActive site residuesB-lactam antibioticsMycobacterium tuberculosisCultures of M. tuberculosisRing openingSite residuesBoronic acidsConstitutive expressionSignificant growth inhibitionStructural characterizationMass spectrometryCompound formsCovalent complexM. tuberculosisGrowth inhibitionBinding inhibitorAcylated formEnzymeRingCompoundsInhibiting the β‑Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs)
Kurz S, Hazra S, Bethel C, Romagnoli C, Caselli E, Prati F, Blanchard J, Bonomo R. Inhibiting the β‑Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs). ACS Infectious Diseases 2015, 1: 234-242. PMID: 27622739, DOI: 10.1021/acsinfecdis.5b00003.Peer-Reviewed Original Research
2012
Reappraising the use of β-lactams to treat tuberculosis
Kurz S, Bonomo R. Reappraising the use of β-lactams to treat tuberculosis. Expert Review Of Anti-infective Therapy 2012, 10: 999-1006. PMID: 23106275, PMCID: PMC3728824, DOI: 10.1586/eri.12.96.Peer-Reviewed Original Research
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