Genome-scale metabolic modeling reveals increased reliance on valine catabolism in clinical isolates of Klebsiella pneumoniae

Abstract

Infections due to carbapenem-resistant Enterobacteriaceae have recently emerged as one of the most urgent threats to hospitalized patients within the United States and Europe. By far the most common etiological agent of these infections is Klebsiella pneumoniae, frequently manifesting in hospital-acquired pneumonia with a mortality rate of [~]50% even with antimicrobial intervention. We performed transcriptomic analysis of data collected from in vitro characterization of both laboratory and clinical isolates revealed shifts in expression of multiple master metabolic regulators across isolate types. Metabolism has been previously shown to be an effective target for antibacterial therapy, and GENREs have provided a powerful means to accelerate identification of potential targets in silico. Combining these techniques with the transcriptome meta-analysis, we generated context-specific models of metabolism utilizing a well-curated GENRE of K. pneumoniae (iYL1228) to identify novel therapeutic targets. Functional metabolic analyses revealed that both composition and metabolic activity of clinical isolate-associated context-specific models significantly differs from laboratory isolate-associated models of the bacterium. Additionally, we identified increased consumption of L-valine in clinical isolate-specific growth simulations. Importantly, valine has been shown to augment macrophage phagocytosis, and this result could be indicative of an immunosuppressive strategy Klebsiella pneumoniae evolved for survival during infection. These findings warrant future studies for potential efficacy of valine transaminase inhibition as a target against K. pneumoniae infection. ImportanceIncidences of infection by Klebsiella pneumoniae have grown in frequency to become the leading agents of CRE infection among hospitalized patients in the United States and Europe. Transcriptomic meta-analysis of data collected from both laboratory and clinical isolates indicated significant shifts in expression of key transcription factors related to metabolism. Metabolic network reconstructions have previously proven effective for quickly identifying potential targets in silico, therefore we combined these approaches by integrating the transcriptomic data from each isolate type into a well-curated GENRE of K. pneumoniae to predict emergent metabolic patterns. Leveraging this systems-biology approach we found discordant patterns of active metabolism between clinical and laboratory isolates, with a striking difference in L-valine catabolism. Exogenous valine is known to increase macrophage phagocytosis, and our results may support immunomodulatory activity in K. pneumoniae evolved to avoid host clearance.