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IRM23NL: Genome-scale metabolic model of Rothia mucilaginosa DSM20746

ABSTRACT: Backtround:Cystic fibrosis (CF) is an inherited genetic disorder caused by the cystic fibrosis transmembrane conductance regulator(CFTR) gene mutation, producing sticky and thick mucosal fluids. This leads to an environment that facilitates the colonization ofopportunistic microorganisms, causing progressive acute and chronic lung infections.Rothia mucilaginosa, an oral commensal, isrelatively abundant in the lungs of CF patients. Recent studies have unveiled the anti-inflammatory effects ofR. mucilaginosausinginvitro3D lung epithelial cell culture andin vivomouse models. Apart from its probiotic effect,R. mucilaginosacan be pathogenic,resulting in severe infections. This dual nature highlights the bacterium’s complexity and diverse impact on health and disease.However, its metabolic capabilities and genotype-phenotype relationships remain largely unknown.Results:To gain insights intoR. mucilaginosa’s cellular metabolism and genetic alterations, we developed the first manually curatedgenome-scale metabolic model,iRM23NL. Through growth kinetic experiments and high-throughput phenotypic microarray testings,we defined its complete catabolic phenome. Subsequently, we assessed the model’s effectiveness in accurately predicting growthbehaviors and utilizing multiple substrates. We used constraint-based modeling techniques to formulate novel hypotheses that couldexpedite the development of antimicrobial strategies. More specifically, we detected putative essential genes and assessed their effecton metabolism under varying nutritional conditions. These predictions could offer novel potential antimicrobial targets without laboriouslarge-scale screening of knock-outs and mutant transposon libraries. Finally, we examined the production levels of enterobactin undervarying nutritional conditions and suggested compounds that could alter its production.Conclusion:Overall,iRM23NL demonstrates a solid capability to predict cellular phenotypes and holds immense potential as avaluable resource for accurate predictions in advancing antimicrobial therapies. Moreover, it can guide the metabolic engineering totailorR. mucilaginosa’s metabolism for desired performance.Availability and implementation:Source code and model are freely accessible from GitHub and BioModels.

SUBMITTER: Andreas Dräger

PROVIDER: MODEL2310240001 | BioModels | 2024-04-10

REPOSITORIES: BioModels

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Project description:To provide a more detailed survey of adaptive changes in the physiology of P. aeruginosa (PA) during long-term infection of the cystic fibrosis (CF) lung, we performed a comparative proteome and transcriptome analysis of a set of isogenic sequential non-mutator and mutator isolates from three selected CF patients. Recently, we showed that during CF lung persistence PA mutators converge to a virulence-attenuated phenotype. In this study, we demonstrate that besides virulence-associated traits (VATs) the adaptation process of PA predominantly comprises metabolic pathways. In end-stage mutator strains, transcripts of genes encoding VATs, chemotaxis, degradation of aromatic compounds and several two-component regulatory systems were decreased. In contrast, several transcripts of genes or proteins involved in metabolism of fatty acids, nucleotides, amino acids and the generation of energy were increased. Of particular interest is the increased expression level of genes involved in (i) the anaerobic arginine-deiminase pathway, (ii) the anaerobic respiration such as nitrate-uptake protein OprF, redox-active azurin and cytchrome c551 peroxidase, (iii) the micro-aerobic respiration such as high oxygen-affinity cytochrome oxidase cbb3 (iv) the tricarboxylic acid cycle (TCA), glyoxylate shunt and anaplerotic carboxylation reactions to oxaloacetate. Strikingly, an increased transcription of the anaerobic regulator gene anr correlates with the up-regulation of ANR-dependent genes. In conclusion, these changes in transcriptome and proteome indicate an adaptive shift towards constitutive expression of genes of metabolic pathways obviously required for growth under micro-aerobic and nutritional conditions of suppurative CF lung tissue. Finally, these results provide us with new targets for antimicrobial agents and biomarkers reflecting adaptation of PA towards progressive CF lung disease. Experiment Overall Design: P. aeruginosa isolates recovered from different time points of chronic cystic fibrosis lung disease were cultered in vitro, harvested for RNA extraction and hybridization on Affymetrix microarrays. We compared the transcriptome (triplicate microarrays) of early non-mutator P. aeruginosa isolates with late mutator isolates with high mutation frequency probably the driving force of an efficient adaptation to changing environements to conclude from differences in gene expression to the requirements of CF lung environment. Experiment Overall Design: Second publication of array data to be added later

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IRM23NL: Genome-scale metabolic model of Rothia mucilaginosa DSM20746

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