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Volume 10, Issue 2

A validated pangenome-scale metabolic model for the species complex Open Access

Abstract

The species complex (KpSC) is a major source of nosocomial infections globally with high rates of resistance to antimicrobials. Consequently, there is growing interest in understanding virulence factors and their association with cellular metabolic processes for developing novel anti-KpSC therapeutics. Phenotypic assays have revealed metabolic diversity within the KpSC, but metabolism research has been neglected due to experiments being difficult and cost-intensive. Genome-scale metabolic models (GSMMs) represent a rapid and scalable approach for exploring metabolic diversity, which compile genomic and biochemical data to reconstruct the metabolic network of an organism. Here we use a diverse collection of 507 KpSC isolates, including representatives of globally distributed clinically relevant lineages, to construct the most comprehensive KpSC pan-metabolic model to date, KpSC pan v2. Candidate metabolic reactions were identified using gene orthology to known metabolic genes, prior to manual curation via extensive literature and database searches. The final model comprised a total of 3550 reactions, 2403 genes and can simulate growth on 360 unique substrates. We used KpSC pan v2 as a reference to derive strain-specific GSMMs for all 507 KpSC isolates, and compared these to GSMMs generated using a prior KpSC pan-reference (KpSC pan v1) and two single-strain references. We show that KpSC pan v2 includes a greater proportion of accessory reactions (8.8 %) than KpSC pan v1 (2.5 %). GSMMs derived from KpSC pan v2 also generate more accurate growth predictions, with high median accuracies of 95.4 % (aerobic, =37 isolates) and 78.8 % (anaerobic, =36 isolates) for 124 matched carbon substrates. KpSC pan v2 is freely available at https://github.com/kelwyres/KpSC-pan-metabolic-model, representing a valuable resource for the scientific community, both as a source of curated metabolic information and as a reference to derive accurate strain-specific GSMMs. The latter can be used to investigate the relationship between KpSC metabolism and traits of interest, such as reservoirs, epidemiology, drug resistance or virulence, and ultimately to inform novel KpSC control strategies.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): bacterial metabolism , genome-scale metabolic models , genomics , Klebsiella and pangenome
Funding
This study was supported by the:
  • National Health and Medical Research Council (Award APP1176192)
    • Principle Award Recipient: KellyL Wyres
  • Australian Research Council (Award DP200103364)
    • Principle Award Recipient: KellyL Wyres
© 2024 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2024-05-20
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A validated pangenome-scale metabolic model for the Klebsiella pneumoniae species complex
M Gen 10, 001206 (2024); https://doi.org/10.1099/mgen.0.001206
/content/journal/mgen/10.1099/mgen.0.001206
/content/journal/mgen/10.1099/mgen.0.001206
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