ABSTRACT
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 Statement
The authors have declared no competing interest.
Footnotes
Experimental data that validate the predicted growth rates in different media for various strains.
List of Abbreviations
- AGORA
- Assembly of Gut Organisms through Reconstruction and Analysis
- AMR
- antimicrobial resistance
- ATP
- adenosine triphosphate
- BiGG
- Biochemical, Genetical, and Genomical
- BLAST
- Basic Local Alignment Search Tool
- BMBF
- Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung)
- BMBF-DZG
- Deutsche Zentren der Gesundheitsforschung
- BOF
- biomass objective function
- CBM
- constraint-based modelling
- CMFI
- Controlling Microbes to Fight Infections
- COBRApy
- Constraints-Based Reconstruction and Analysis for Python
- CoA
- coenzyme A
- COVID-19
- Coronavirus Disease 2019
- CTP
- cytidine triphosphate
- CV
- controlled vocabulary
- DFG
- Deutsche Forschungsgemeinschaft
- DZIF
- German Center for Infection Research
- ECO
- Evidence and Conclusion Ontology
- EDR
- energy dissipation reaction
- EGC
- energy-generating cycle
- EPSP
- enolpyruvylshikimate phosphate
- FADH2
- flavin adenine dinucleotide
- FAIR
- Findable, Accessible, Interoperable, and Reusable
- FC
- fold change
- FMNH2
- flavin mononucleotide
- FBA
- flux balance analysis
- fbc
- flux balance constraints
- FDA
- Food and Drug Administration
- FN
- false negative
- FP
- false positive
- GEM
- genome-scale metabolic model
- GFF
- General Feature Format
- GMP
- guanosine 5’-phosphate
- GPR
- gene-protein-reaction associations
- GTP
- guanosine triphosphate
- ICU
- intensive care unit
- INSeq
- insertion sequencing
- ITP
- inosine triphosphate
- JSON
- JavaScript Object Notation
- KDPG
- 2-keto-3-deoxy-6-phosphogluconate
- KEGG
- Kyoto Encyclopedia of Genes and Genomes
- LB
- Luria-Bertani
- M9
- M9 minimal medium
- MDR
- multidrug-resistant
- MEMOTE
- Metabolic Model Testing
- MIRIAM
- Minimal Information Required In the Annotation of Models
- MOMA
- Minimization of Metabolic Adjustment
- NADH
- nicotinamide adenine dinucleotide
- NADPH
- nicotinamide adenine dinucleotide phosphate
- NCBI
- National Centre for Biotechnology Information
- OD
- optical density
- OLS
- Ontology Lookup Service
- OMEX
- Open Modelling EXchange format
- PATRIC
- Pathosystems Resource Integration Center
- PBS
- phosphate buffered saline
- DR
- pandrug-resistant
- SARS-CoV-2
- Severe Acute Respiratory Syndrome Coronavirus 2
- SBML
- Systems Biology Markup Language
- SBO
- Systems Biology Ontology
- SNM
- synthetic nasal medium
- TN
- true negative
- TP
- true positive
- UTP
- uridine triphosphate
- VMH
- Virtual Metabolic Human
- WHO
- World Health Organization
- XDR
- extensively drug-resistant
