RT Journal Article SR Electronic T1 Exploring the metabolic profiling of A. baumannii for antimicrobial development using genome-scale modeling 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 Dräger, Andreas YR 2023 UL http://biorxiv.org/content/early/2023/09/15/2023.09.13.557502.abstract AB With the emergence of multidrug-resistant bacteria, the World Health Organization published a catalog of microorganisms in 2017 for which new antibiotics are urgently needed. Within this list, the carbapenem-resistant pathogen Acinetobacter baumannii, belonging to the ESKAPE group, has been granted the “critical” status. Over the years, such isolates have been detected within healthcare units, posing a global threat to upcoming pandemics. One way to facilitate a systemic view of bacterial metabolism and allow the development of new therapeutics based on environmental and genetic alterations is to apply constraint-based modeling on metabolic networks. 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 with an accuracy of over 80%, while positive biomass production rates were observed in growth media relevant to A. baumannii. Additionally, we identified putative essential genes with no human counterparts, which could serve as novel antibiotic candidates for the development of future antimicrobial strategies. Finally, we have assembled the first curated collection of available reconstructions for distinct A. baumannii strains and analyzed their growth characteristics. The presented models herein are in a standardized and well-curated format, facilitating their usability, while they can be used to guide the reconstruction of multi-strain networks. Ultimately, they serve as a knowledge base for reliable predictions under various perturbations and the development of effective drugs.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 modelingCMFIControlling 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 FormatGPRgene-protein-reaction associationsGTPguanosine triphosphateICUintensive care unitINSeqinsertion sequencingITPinosine triphosphateKDPG2-keto-3-deoxy-6-phosphogluconateKEGGKyoto Encyclopedia of Genes and GenomesLBLuria-BertaniMDRmultidrug-resistantMEMOTEMetabolic Model TestingMIRIAMMinimal Information Required In the Annotation of ModelsMOMAMinimization of Metabolic AdjustmentNADHnicotinamide adenine dinucleotideNADPHnicotinamide adenine dinucleotide phosphateNCBINational Centre for Biotechnology InformationOLSOntology Lookup ServiceOMEXOpen Modeling EXchange formatPATRICPathosystems Resource Integration CenterPDRpandrug-resistantSARS-CoV-2Severe Acute Respiratory Syndrome Coronavirus 2SBOSystems Biology OntologySNMsynthetic nasal mediumTNtrue negativeTPtrue positiveUTPuridine triphosphateVMHVirtual Metabolic HumanWHOWorld Health OrganizationXDRextensively drug-resistant