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Deciphering the Metabolic Responses to Polymyxin Killing Using a High EP0921 Deciphering the metabolic responses to polymyxin killing using a high-quality genome-scale metabolic model for an opportunistic pathogen Pseudomonas aeruginosa PAO1 Yan Zhu1, Tobias Czauderna2, Matthias Klapperstueck2, Meiling Han3, Jing Lu4, Tony Velkov3, Trevor Lithgow1, Jiangning Song1, Falk Schreiber2,5, Jian Li1 1 Infection and Immunity Program, Biomedicine Discovery Institute, Faculty of Medicine, Nursing & Health Sciences, Monash University, Melbourne, Australia; 2 Faculty of Information Technology, Monash University, Melbourne, Australia; 3 Monash Institute of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia; 4 School of Psychological Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Melbourne, Australia; 5 Department of Computer and Information Science, University of Konstanz, Konstanz, Germany PM1 (carbon) Biolog iPAO1 PM1 (carbon) Biolog iPAO1 PM3 (nitrogen)Biolog iPAO1 INTRODUCTION L-Arabinose × × Chondroitin Sulfate C × × Ammonia √ √ properties (Fig 3). N-Acetyl-D-Glucosamine √ √ α-Cyclodextrin × × Nitrite √ √ D-Saccharic Acid × × β-Cyclodextrin × × Sodium Nitrate √ √ • Pseudomonas aeruginosa is a Gram-negative opportunistic Succinic Acid √ √ γ-Cyclodextrin × × Urea √ √ • Integrative modelling with transcriptomics data D-Galactose × × Dextrin × × Biuret × × L-Aspartic Acid √ √ Gelatin × × L-Alanine √ √ pathogen with a high incidence in immunocompromised patients. L-Proline √ √ Glycogen × × L-Arginine √ √ showed polymyxin resulted in enhanced redox, D-Alanine √ √ Inulin × × L-Asparagine √ √ D-Trehalose × √ Laminarin × × L-Aspartic Acid √ √ D-Mannose × × Mannan × × L-Cysteine √ √ • Polymyxins have revived as the last-line therapy to treat infections Dulcitol × × Pectin × × L-Glutamic Acid √ √ reduced growth and energy generation. D-Serine × √ N-Acetyl-D-Galactosamine × × L-Glutamine √ √ D-Sorbitol × × N-Acetyl-Neuraminic Acid × × Glycine √ √ caused by Gram-negative ‘superbugs’. Glycerol √ √ β-D-Allose × × L-Histidine √ √ • P. aeruginosa may generate redox power to combat L-Fucose × × D-Amygdalin × × L-Isoleucine √ √ D-Glucuronic Acid × × D-Arabinose × × L-Leucine √ √ D-Gluconic Acid √ √ D-Arabitol × × L-Lysine √ √ • The emergence of polymyxin resistance in P. aeruginosa has been D,L-α-Glycerol Phosphate × √ L-Arabitol × × L-Methionine √ √ oxidative stress induced by polymyxins (Fig 4). D-Xylose × × Arbutin × × L-Phenylalanine √ √ L-Lactic Acid √ √ 2-Deoxy-D-Ribose × × L-Proline √ √ reported worldwide. Formic Acid √ √ i-Erythritol × × L-Serine √ √ D-Mannitol √ √ D-Fucose × × L-Threonine √ √ CONCLUSIONS L-Glutamic Acid √ √ 3-O-β-D-Galacto-pyranosyl-D-Arabinose × × L-Tryptophan √ √ D-Glucose-6-Phosphate × √ Gentiobiose × × L-Tyrosine √ √ • Genome-scale metabolic model (GSMM) enables accurate D-Galactonic Acid-γ-Lactone × × L-Glucose × × L-Valine √ √ • A high-quality GSMM iPAO1 was developed, with D,L-Malic Acid √ √ Lactitol × × D-Alanine √ √ Fig 3. Simulation of the D-Ribose √ √ D-Melezitose × × D-Asparagine √ √ predictions of metabolic responses to antibiotic treatments at Tween 20 √ × Maltitol × × D-Aspartic Acid × × which the predictions of the growth phenotypes L-Rhamnose × × α-Methyl-D-Galactoside × × D-Glutamic Acid √ √ impacts of lipid A D-Fructose √ √ β-Methyl-D-Galactoside × × D-Lysine √ √ system level. Acetic Acid √ √ 3-Methyl Glucose × × D-Serine √ √ D-(+)-Glucose √ √ β-Methyl-D-Glucuronic Acid × × D-Valine √ √ modifications on bacterial and gene essentiality showed high accuracy. Maltose × × α-Methyl-D-Mannoside × × L-Citrulline √ √ D-Melibiose × × β-Methyl-D-Xyloside × × L-Homoserine × √ MATERIALS AND METHODS Thymidine × × Palatinose × × L-Ornithine √ √ growth, metabolism and OM • Integration with transcriptomics data elucidated L-Asparagine √ √ D-Raffinose × × N-Acetyl-L-Glutamic Acid √ √ D-Aspartic Acid × × Salicin × × N-Phthaloyl-L-Glutamic Acid √ × • GSMM (iPAO1) was reconstructed for type strain PAO1 by merging D-Glucosaminic Acid × × Sedoheptulosan × × L-Pyroglutamic Acid √ √ the metabolic responses to polymyxins. 1,2-Propanediol √ √ L-Sorbose × × Hydroxylamine × √ physiochemical properties. Tween 40 √ × Stachyose × × Methylamine × × α-Keto-Gutaric Acid √ √ D-Tagatose × × N-Amylamine × × two previous models, followed by extensive manual curation. α-Ketobutyric Acid √ √ Turanose × × N-Butylamine × × • The metabolic impacts of lipid A modifications • Overall, iPAO1 provides a powerful tool for α-Methyl-D-Galactoside × × Xylitol × × Ethylamine × × α-D-Lactose × × N-Acetyl-D-glucosaminitol × × Ethanolamine √ × • The growth capability on various nutrients was predicted using Lactulose × × γ-Amino Butyric Acid √ √ Ethylenediamine × × were calculated using experimentally obtained investigation of antibiotic killing and resistance, Sucrose × × δ-Amino Valeric Acid √ √ Putrescine √ √ Uridine × √ Butyric Acid √ √ Agmatine √ √ flux balance analysis and validated using BIOLOG assays. L-Glutamine √ √ Capric Acid × √ Histamine √ √ and randomly generated lipid A compositions. and has significant application potential in systems m-Tartaric Acid × × Caproic Acid √ √ β-Phenylethylamine √ √ D-Glucose-1-Phosphate × √ Citraconic Acid × × Tyramine √ √ D-Fructose-6-Phosphate × × Citramalic Acid √ √ Acetamide √ √ 1 pharmacology. • The gene essentiality was predicted by in silico single-gene Tween 80 √ × D-Glucosamine × × Formamide × × • iPAO1 was integrated with transcriptomics data α-Hydroxy Glutaric Acid-γ-Lactone × × 2-Hydroxybenzoic acid × × Glucuronamide √ √ Oxidative phosphorylation D,L-α-Hydroxy-Butyric Acid √ √ 4-Hydroxy Benzoic Acid Sodium √ √ D,L-Lactamide √ √ Periplasm 2 Gluconeogenesis + + + β-Methyl-D-Glucoside × × β-Hydroxy Butyric Acid √ √ D-Glucosamine × × using E-Flux method to elucidate the metabolic H H H deletion and validated using two transposon insertion libraries. NADH Ubiquinol-8 Cytochrome c2 O2 Adonitol × × γ-Hydroxy Butyric Acid × √ D-Galactosamine × × Glucose 6-pohsophate Maltotriose × × 2-Oxovaleric acid × × D-Mannosamine × × OM 2'-Deoxy Adenosine × × Itaconic Acid √ √ N-Acetyl-D-Glucosamine √ √ responses to polymyxins. Fructose 6-phosphate + Adenosine √ √ 5-Keto-D-Gluconic Acid × × N-Acetyl-D-Galactosamine √ √ NAD Ubiquinone-8 Cytochrome c3 H2O Glycyl-L-Aspartic Acid × √ D-Lactic Acid Methyl Ester × × N-Acetyl-D-Mannosamine × × ADP ATP Cytoplasm H+ Citric Acid √ √ Malonic Acid √ √ Adenine √ √ Complex I Complex III Complex IV ATPase m-Inositol × × Melibionic Acid × × Adenosine √ √ RESULTS AND DISCUSSION D-Threonine × × Oxolic Acid × × Cytidine √ √ Glyceraldehyde 3-phosphate Acetyl-CoA Fumaric Acid √ √ Oxalomalic Acid × × Cytosine √ √ Oxaloacetate Bromo Succinic Acid √ × Quinic Acid √ √ Guanine √ √ NADH Citrate Propionic Acid √ √ D-Ribono-1,4-Lactone × × Guanosine √ √ • The constructed iPAO1 contains 3022 metabolites, 1,3-Biphosphateglycerate Mucic Acid × × Sebacic Acid × × Thymine √ √ NADH Glycolic Acid × × Sorbic acid √ √ Thymidine × × ATP NADH Acetyl-CoA Glyoxylic Acid × × Succinamic Acid √ √ Uracil √ √ 3-Phosphoglycerate 4265 reactions and 1458 genes, representing the most Glyoxalate Malate Tricarboxylic acid Isocitrate Turnover rate of cofactors D-Cellobiose × × D-Tartaric Acid × × Uridine √ √ cycle ATP NADH NADPH Ubiquinol-8 Inosine √ √ L-Tartaric Acid × × Inosine √ √ Serine/glycine biosynthesis Glycyl-L-Glutamic Acid × √ Acetamide × √ Xanthine √ √ Fumarate NADH comprehensive GSMM for P. aeruginosa thus far. α-ketoglutarate Tricarballylic Acid × × L-Alaninamide √ √ Xanthosine √ √ GTP L-Serine √ √ N-Acetyl-L-Glutamic Acid √ √ Uric Acid √ √ QH2 NADH ATP Succinate L-Threonine × √ L-Arginine √ √ Alloxan √ × Pyruvate Succinyl-CoA L-Alanine √ √ Glycine √ √ Allantoin √ √ • iPAO1 features by significant expansion of metabolic Ala-Gly × √ L-Histidine √ √ Parabanic Acid √ × Acetoacetic Acid √ √ L-Homoserine × √ D,L-α-Amino-N-Butyric Acid × × N-Acetyl-D-Mannosamine × × Hydroxy-L-Proline √ √ γ-Amino Butyric Acid √ √ pathways including glycerophospholipids and Mono Methyl Succinate √ √ L-Isoleucine √ √ ε-Amino-N-Caproic Acid × × Methyl Pyruvate √ × L-Leucine √ √ D,L-a-Amino- Caprylic Acid × × Fig 4. Flux changes induced by polymyxin treatment. D-Malic Acid × × L-Lysine × √ δ-Amino-N-Valeric Acid √ √ lipopolysaccharides (LPS) biosynthesis (Fig 1). L-Malic Acid √ √ L-Methionine × √ α-Amino-N-Valeric Acid √ × Glycyl-L-Proline √ √ L-Ornithine √ √ Ala-Asp √ √ p-Hydroxy Phenyl Acetic Acid √ √ L-Phenylalanine × √ Ala-Gln √ √ • Prediction of the growth phenotypes on 190 carbon REFERENCES M-Hydroxy Phenyl Acetic Acid × × L-Pyroglutamic Acid √ √ Ala-Glu √ √ Tyramine √ √ L-Valine × √ Ala-Gly √ √ D-Psicose × × D,L-Carnitine √ √ Ala-His √ √ L-Lyxose × × Sec-Butylamine × × Ala-Leu √ √ and 95 nitrogen nutrients showed an overall accuracy 1. Maifiah, MHM et al. Manuscript to be submitted. 2017. 2. Colijn, C et al. Glucuronamide × × D.L-Octopamine √ √ Ala-Thr √ √ Pyruvic Acid √ √ Putrescine √ √ Gly-Asn √ √ L-Galactonic Acid-γ-Lactone × × Dihydroxy Acetone × × Gly-Gln √ √ of 89.1% (Fig 2), which outperformed all the previous PLoS Comput Biol 2009; 5: e1000489. 3. Oberhardt, MA et al. J Bacteriol D-Galacturonic Acid × × 2,3-Butanediol √ √ Gly-Glu √ √ β-Phenylethylamine × × Diacetyl × × Gly-Met × √ 3-5 2-Aminoethanol √ √ 3-Hydroxy 2-Butanone × × Met-Ala √ √ GSMMs for P. aeruginosa . 2008; 190: 2790. 4. Oberhardt, MA et al. PLoS Comput Biol 2011; 7: Fig 1. LPS biosynthesis in iPAO1. (A) VANTED diagram showing Fig 2. Comparison of BIOLOG results • Prediction of gene essentiality analysis achieved a e1001116. 5. Henry, CS et al. Nat Biotechnol 2010; 28: 977. the biosynthesis of different LPS; Metabolites, circles; reactions, (left) and model prediction (right). Blue high accuracy of 87.9%. ACKNOWLEDGEMENTS squares. (B) LPS biosynthesis pathway; The lipid A and LPS indicates growth; whereas yellow • Lipid A modifications resulted in minor metabolic Interdisciplinary Grant from Monash University and Travel Award from species shown here are indicated by the same colors as in (A). indicates no-growth. fluxes changes and altered OM physiochemical Monash Biomedicine Discovery Institute..
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