RT Journal Article
SR Electronic
T1 Exploring the metabolic profiling of <em>A. baumannii</em> for antimicrobial development using genome-scale modelling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.09.13.557502
DO 10.1101/2023.09.13.557502
A1 Leonidou, Nantia
A1 Xia, Yufan
A1 Friedrich, Lea
A1 Schütz, Monika S.
A1 Dräger, Andreas
YR 2024
UL http://biorxiv.org/content/early/2024/02/07/2023.09.13.557502.abstract
AB With the emergence of multidrug-resistant bacteria, the World Health Organization published a catalog of microorganisms urgently needing new antibiotics, with the carbapenem-resistant Acinetobacter baumannii designated as “critical”. Such isolates, frequently detected in healthcare settings, pose a global pandemic threat. One way to facilitate a systemic view of bacterial metabolism and allow the development of new therapeutics is to apply constraint-based modelling. Here, we developed a versatile workflow to build high-quality and simulation-ready genome-scale metabolic models. We applied our workflow to create a novel metabolic model for A. baumannii and validated its predictive capabilities using experimental nutrient utilization and gene essentiality data. Our analysis showed that our model i ACB23LX could recapitulate cellular metabolic phenotypes observed during in vitro experiments, while positive biomass production rates were observed and experimentally validated in various growth media. We further defined a minimal set of compounds that increase A. baumannii ‘s cellular biomass and identified putative essential genes with no human counterparts, offering novel candidates for future antimicrobial development. Finally, we assembled and curated the first collection of reconstructions for distinct A. baumannii strains and analysed their growth characteristics. The presented models are in a standardised and well-curated format, enhancing their usability for multi-strain network reconstruction.Competing Interest StatementThe authors have declared no competing interest.AGORAAssembly of Gut Organisms through Reconstruction and AnalysisAMRantimicrobial resistanceATPadenosine triphosphateBiGGBiochemical, Genetical, and GenomicalBLASTBasic Local Alignment Search ToolBMBFFederal Ministry of Education and Research (Bundesministerium für Bildung und Forschung)BMBF-DZGDeutsche Zentren der GesundheitsforschungBOFbiomass objective functionCBMconstraint-based modellingCMFIControlling Microbes to Fight InfectionsCOBRApyConstraints-Based Reconstruction and Analysis for PythonCoAcoenzyme ACOVID-19Coronavirus Disease 2019CTPcytidine triphosphateCVcontrolled vocabularyDFGDeutsche ForschungsgemeinschaftDZIFGerman Center for Infection ResearchECOEvidence and Conclusion OntologyEDRenergy dissipation reactionEGCenergy-generating cycleEPSPenolpyruvylshikimate phosphateFADH2flavin adenine dinucleotideFAIRFindable, Accessible, Interoperable, and ReusableFCfold changeFMNH2flavin mononucleotideFBAflux balance analysisfbcflux balance constraintsFDAFood and Drug AdministrationFNfalse negativeFPfalse positiveGEMgenome-scale metabolic modelGFFGeneral Feature FormatGMPguanosine 5’-phosphateGPRgene-protein-reaction associationsGTPguanosine triphosphateICUintensive care unitINSeqinsertion sequencingITPinosine triphosphateJSONJavaScript Object NotationKDPG2-keto-3-deoxy-6-phosphogluconateKEGGKyoto Encyclopedia of Genes and GenomesLBLuria-BertaniM9M9 minimal mediumMDRmultidrug-resistantMEMOTEMetabolic Model TestingMIRIAMMinimal Information Required In the Annotation of ModelsMOMAMinimization of Metabolic AdjustmentNADHnicotinamide adenine dinucleotideNADPHnicotinamide adenine dinucleotide phosphateNCBINational Centre for Biotechnology InformationODoptical densityOLSOntology Lookup ServiceOMEXOpen Modelling EXchange formatPATRICPathosystems Resource Integration CenterPBSphosphate buffered salineDRpandrug-resistantSARS-CoV-2Severe Acute Respiratory Syndrome Coronavirus 2SBMLSystems Biology Markup LanguageSBOSystems Biology OntologySNMsynthetic nasal mediumTNtrue negativeTPtrue positiveUTPuridine triphosphateVMHVirtual Metabolic HumanWHOWorld Health OrganizationXDRextensively drug-resistant