Genome-scale metabolic modeling of responses to polymyxins in<i>Pseudomonas aeruginosa</i>

Zhu, Yan; Czauderna, Tobias; Zhao, Jinxin; Klapperstueck, Matthias; Maifiah, Mohd Hafidz Mahamad; Han, Mei‐Ling; Lü, Jing; Sommer, Björn; Velkov, Tony; Lithgow, Trevor; Song, Jiangning; Schreiber, Falk; Li, Jian

doi:10.1093/gigascience/giy021

Cited by 47 publications

(41 citation statements)

References 96 publications

(143 reference statements)

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“…Systems pharmacology has been extensively used for understanding bacterial physiology and mechanisms of antibiotic killing and resistance ( Henry et al, 2015 ; Maifiah et al, 2017 ; Zampieri et al, 2017 ; Zhu et al, 2018 ). In particular, metabolomics provides a powerful systems tool to identify and quantify key intracellular metabolites at the network level in responses to antibiotics ( Kaddurah-Daouk et al, 2008 ; Maifiah et al, 2017 ; Zampieri et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii

et al. 2018

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Background: Polymyxins are a last-line class of antibiotics against multidrug-resistant Acinetobacter baumannii; however, polymyxin resistance can emerge with monotherapy. Therefore, synergistic combination therapy is a crucial strategy to reduce polymyxin resistance.Methods: This study conducted untargeted metabolomics to investigate metabolic responses of a multidrug-resistant (MDR) A. baumannii clinical isolate, AB090342, to colistin and aztreonam alone, and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics; metabolites showing ≥ 2-fold changes were subjected to bioinformatics analysis.Results: The synergistic action of colistin-aztreonam combination was initially driven by colistin via significant disruption of bacterial cell envelope, with decreased phospholipid and fatty acid levels at 1 h. Cell wall biosynthesis was inhibited at 4 and 24 h by aztreonam alone and the combination as shown by the decreased levels of two amino sugars, UDP-N-acetylglucosamine and UDP-N-acetylmuramate; these results suggested that aztreonam was primarily responsible for the synergistic killing at later time points. Moreover, aztreonam alone and the combination significantly depleted pentose phosphate pathway, amino acid, peptide and nucleotide metabolism, but elevated fatty acid and key phospholipid levels. Collectively, the combination synergy between colistin and aztreonam was mainly due to the inhibition of cell envelope biosynthesis via different metabolic perturbations.Conclusion: This metabolomics study is the first to elucidate multiple cellular pathways associated with the time-dependent synergistic action of colistin-aztreonam combination against MDR A. baumannii. Our results provide important mechanistic insights into optimizing synergistic colistin combinations in patients.

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Section: Introductionmentioning

confidence: 99%

Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii

et al. 2018

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“…In this study, we investigated the secondary effects of the NalD mutation by integrating metabolic modeling and transcriptomics data. Over the last decade, metabolic network analysis that combines genome-scale metabolic models and omics data have been applied to study antibiotic resistance in bacteria and to suggest therapeutic targets [46][47][48][49][50]. Although the molecular (primary) function of the NalD mutation has been widely studied, our work adds to our limited understanding of its secondary effects.…”

Section: Discussionmentioning

confidence: 99%

Systems-level analysis of NalD mutation, a recurrent driver of rapid drug resistance in acute Pseudomonas aeruginosa infection

et al. 2019

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Pseudomonas aeruginosa, a main cause of human infection, can gain resistance to the antibiotic aztreonam through a mutation in NalD, a transcriptional repressor of cellular efflux. Here we combine computational analysis of clinical isolates, transcriptomics, metabolic modeling and experimental validation to find a strong association between NalD mutations and resistance to aztreonam-as well as resistance to other antibiotics-across P. aeruginosa isolated from different patients. A detailed analysis of one patient's timeline shows how this mutation can emerge in vivo and drive rapid evolution of resistance while the patient received cancer treatment, a bone marrow transplantation, and antibiotics up to the point of causing the patient's death. Transcriptomics analysis confirmed the primary mechanism of NalD action-a loss-of-function mutation that caused constitutive overexpression of the MexAB-OprM efflux system-which lead to aztreonam resistance but, surprisingly, had no fitness cost in the absence of the antibiotic. We constrained a genome-scale metabolic model using the transcriptomics data to investigate changes beyond the primary mechanism of resistance, including adaptations in major metabolic pathways and membrane transport concurrent with aztreonam resistance, which may explain the lack of a fitness cost. We propose that metabolic adaptations may allow resistance mutations to endure in the absence of antibiotics and could be targeted by future therapies against antibiotic resistant pathogens.

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“…The constructed GSMM i AB5075 was then employed to predict the bacterial growth on a chemically defined media with 190 individual carbon sources and 95 nitrogen sources using flux balance analysis (FBA) method with COBRA toolbox 3.0 [ 23 ]. Biomass formation was optimized with the maximum specific carbon nutrient uptake rate set at 10 mmol·gDW −1 ·h −1 under aerobic condition [ 24 ]:

where

represents the stoichiometric matrix with m metabolites and n reactions. Each flux

is constrained by the lower bound

and upper bound

.…”

Section: Methodsmentioning

confidence: 99%

Genome-Scale Metabolic Modeling Reveals Metabolic Alterations of Multidrug-Resistant Acinetobacter baumannii in a Murine Bloodstream Infection Model

et al. 2020

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Multidrug-resistant (MDR) Acinetobacter baumannii is a critical threat to human health globally. We constructed a genome-scale metabolic model iAB5075 for the hypervirulent, MDR A. baumannii strain AB5075. Predictions of nutrient utilization and gene essentiality were validated using Biolog assay and a transposon mutant library. In vivo transcriptomics data were integrated with iAB5075 to elucidate bacterial metabolic responses to the host environment. iAB5075 contains 1530 metabolites, 2229 reactions, and 1015 genes, and demonstrated high accuracies in predicting nutrient utilization and gene essentiality. At 4 h post-infection, a total of 146 metabolic fluxes were increased and 52 were decreased compared to 2 h post-infection; these included enhanced fluxes through peptidoglycan and lipopolysaccharide biosynthesis, tricarboxylic cycle, gluconeogenesis, nucleotide and fatty acid biosynthesis, and altered fluxes in amino acid metabolism. These flux changes indicate that the induced central metabolism, energy production, and cell membrane biogenesis played key roles in establishing and enhancing A. baumannii bloodstream infection. This study is the first to employ genome-scale metabolic modeling to investigate A. baumannii infection in vivo. Our findings provide important mechanistic insights into the adaption of A. baumannii to the host environment and thus will contribute to the development of new therapeutic agents against this problematic pathogen.

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Genome-scale metabolic modeling of responses to polymyxins inPseudomonas aeruginosa

Abstract: Overall, iPAO1 represents the most comprehensive GSMM constructed to date for Pseudomonas. It provides a powerful systems pharmacology platform for the elucidation of complex killing mechanisms of antibiotics.

Cited by 47 publications

References 96 publications

Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii

Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii

Systems-level analysis of NalD mutation, a recurrent driver of rapid drug resistance in acute Pseudomonas aeruginosa infection

Genome-Scale Metabolic Modeling Reveals Metabolic Alterations of Multidrug-Resistant Acinetobacter baumannii in a Murine Bloodstream Infection Model

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