Mechanistic insights into bacterial metabolic reprogramming from omics-integrated genome-scale models.

Understanding the adaptive responses of individual bacterial strains is crucial for microbiome engineering approaches that introduce new functionalities into complex microbiomes, such as xenobiotic compound metabolism for soil bioremediation. Adaptation requires metabolic reprogramming of the cell, which can be captured by multi-omics, but this data remains formidably challenging to interpret and predict. Here we present a new approach that combines genome-scale metabolic modeling with transcriptomics and exometabolomics, both of which are common tools for studying dynamic population behavior. As a realistic demonstration, we developed a genome-scale model of Pseudomonas veronii 1YdBTEX2, a candidate bioaugmentation agent for accelerated metabolism of mono-aromatic compounds in soil microbiomes, while simultaneously collecting experimental data of P. veronii metabolism during growth phase transitions. Predictions of the P. veronii growth rates and specific metabolic processes from the integrated model closely matched experimental observations. We conclude that integrative and network-based analysis can help build predictive models that accurately capture bacterial adaptation responses. Further development and testing of such models may considerably improve the successful establishment of bacterial inoculants in more complex systems

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

A Deep Learning Approach to Antibiotic Discovery

Due to the rapid emergence of antibiotic-resistant bacteria, there is a growing need to discover new antibiotics. To address this challenge, we trained a deep neural network capable of predicting molecules with antibacterial activity. We performed predictions on multiple chemical libraries and discovered a molecule from the Drug Repurposing Hub—halicin—that is structurally divergent from conventional antibiotics and displays bactericidal activity against a wide phylogenetic spectrum of pathogens including Mycobacterium tuberculosis and carbapenem-resistant Enterobacteriaceae. Halicin also effectively treated Clostridioides difficile and pan-resistant Acinetobacter baumannii infections in murine models. Additionally, from a discrete set of 23 empirically tested predictions from >107 million molecules curated from the ZINC15 database, our model identified eight antibacterial compounds that are structurally distant from known antibiotics. This work highlights the utility of deep learning approaches to expand our antibiotic arsenal through the discovery of structurally distinct antibacterial molecules. A trained deep neural network predicts antibiotic activity in molecules that are structurally different from known antibiotics, among which Halicin exhibits efficacy against broad-spectrum bacterial infections in mice.Defence Threat Reduction Agency (Grant HDTRA1-15- 1-0051

Towards human cell simulation

The faithful reproduction and accurate prediction of the phenotypes and emergent behaviors of complex cellular systems are among the most challenging goals in Systems Biology. Although mathematical models that describe the interactions among all biochemical processes in a cell are theoretically feasible, their simulation is generally hard because of a variety of reasons. For instance, many quantitative data (e.g., kinetic rates) are usually not available, a problem that hinders the execution of simulation algorithms as long as some parameter estimation methods are used. Though, even with a candidate parameterization, the simulation of mechanistic models could be challenging due to the extreme computational effort required. In this context, model reduction techniques and High-Performance Computing infrastructures could be leveraged to mitigate these issues. In addition, as cellular processes are characterized by multiple scales of temporal and spatial organization, novel hybrid simulators able to harmonize different modeling approaches (e.g., logic-based, constraint-based, continuous deterministic, discrete stochastic, spatial) should be designed. This chapter describes a putative unified approach to tackle these challenging tasks, hopefully paving the way to the definition of large-scale comprehensive models that aim at the comprehension of the cell behavior by means of computational tools

Towards human cell simulation

none14siThe faithful reproduction and accurate prediction of the phe-notypes and emergent behaviors of complex cellular systems are among the most challenging goals in Systems Biology. Although mathematical models that describe the interactions among all biochemical processes in a cell are theoretically feasible, their simulation is generally hard because of a variety of reasons. For instance, many quantitative data (e.g., kinetic rates) are usually not available, a problem that hinders the execution of simulation algorithms as long as some parameter estimation methods are used. Though, even with a candidate parameterization, the simulation of mechanistic models could be challenging due to the extreme computational effort required. In this context, model reduction techniques and High-Performance Computing infrastructures could be leveraged to mitigate these issues. In addition, as cellular processes are characterized by multiple scales of temporal and spatial organization, novel hybrid simulators able to harmonize different modeling approaches (e.g., logic-based, constraint-based, continuous deterministic, discrete stochastic, spatial) should be designed. This chapter describes a putative unified approach to tackle these challenging tasks, hopefully paving the way to the definition of large-scale comprehensive models that aim at the comprehension of the cell behavior by means of computational tools.noneSpolaor, Simone; Gribaudo, Marco; Iacono, Mauro; Kadavy, Tomas; Oplatková, Zuzana Komínková; Mauri, Giancarlo; Pllana, Sabri; Senkerik, Roman; Stojanovic, Natalija; Turunen, Esko; Viktorin, Adam; Vitabile, Salvatore; Zamuda, Aleš; Nobile, Marco S.Spolaor, Simone; Gribaudo, Marco; Iacono, Mauro; Kadavy, Tomas; Oplatková, Zuzana Komínková; Mauri, Giancarlo; Pllana, Sabri; Senkerik, Roman; Stojanovic, Natalija; Turunen, Esko; Viktorin, Adam; Vitabile, Salvatore; Zamuda, Aleš; Nobile, Marco S

Towards human cell simulation

The faithful reproduction and accurate prediction of the phe-notypes and emergent behaviors of complex cellular systems are among the most challenging goals in Systems Biology. Although mathematical models that describe the interactions among all biochemical processes in a cell are theoretically feasible, their simulation is generally hard because of a variety of reasons. For instance, many quantitative data (e.g., kinetic rates) are usually not available, a problem that hinders the execution of simulation algorithms as long as some parameter estimation methods are used. Though, even with a candidate parameterization, the simulation of mechanistic models could be challenging due to the extreme computational effort required. In this context, model reduction techniques and High-Performance Computing infrastructures could be leveraged to mitigate these issues. In addition, as cellular processes are characterized by multiple scales of temporal and spatial organization, novel hybrid simulators able to harmonize different modeling approaches (e.g., logic-based, constraint-based, continuous deterministic, discrete stochastic, spatial) should be designed. This chapter describes a putative unified approach to tackle these challenging tasks, hopefully paving the way to the definition of large-scale comprehensive models that aim at the comprehension of the cell behavior by means of computational tools

Bioenergetics-based modeling of Plasmodium falciparum metabolism reveals its essential genes, nutritional requirements, and thermodynamic bottlenecks.

Novel antimalarial therapies are urgently needed for the fight against drug-resistant parasites. The metabolism of malaria parasites in infected cells is an attractive source of drug targets but is rather complex. Computational methods can handle this complexity and allow integrative analyses of cell metabolism. In this study, we present a genome-scale metabolic model (iPfa) of the deadliest malaria parasite, Plasmodium falciparum, and its thermodynamics-based flux analysis (TFA). Using previous absolute concentration data of the intraerythrocytic parasite, we applied TFA to iPfa and predicted up to 63 essential genes and 26 essential pairs of genes. Of the 63 genes, 35 have been experimentally validated and reported in the literature, and 28 have not been experimentally tested and include previously hypothesized or novel predictions of essential metabolic capabilities. Without metabolomics data, four of the genes would have been incorrectly predicted to be non-essential. TFA also indicated that substrate channeling should exist in two metabolic pathways to ensure the thermodynamic feasibility of the flux. Finally, analysis of the metabolic capabilities of P. falciparum led to the identification of both the minimal nutritional requirements and the genes that can become indispensable upon substrate inaccessibility. This model provides novel insight into the metabolic needs and capabilities of the malaria parasite and highlights metabolites and pathways that should be measured and characterized to identify potential thermodynamic bottlenecks and substrate channeling. The hypotheses presented seek to guide experimental studies to facilitate a better understanding of the parasite metabolism and the identification of targets for more efficient intervention