ABSTRACT
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 Statement
The authors have declared no competing interest.
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 modeling
- 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
- GPR
- gene-protein-reaction associations
- GTP
- guanosine triphosphate
- ICU
- intensive care unit
- INSeq
- insertion sequencing
- ITP
- inosine triphosphate
- KDPG
- 2-keto-3-deoxy-6-phosphogluconate
- KEGG
- Kyoto Encyclopedia of Genes and Genomes
- LB
- Luria-Bertani
- 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
- OLS
- Ontology Lookup Service
- OMEX
- Open Modeling EXchange format
- PATRIC
- Pathosystems Resource Integration Center
- PDR
- pandrug-resistant
- SARS-CoV-2
- Severe Acute Respiratory Syndrome Coronavirus 2
- 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
