Origin of biogeographically distinct ecotypes during laboratory evolution.

Resource partitioning is central to the incredible productivity of microbial communities, including gigatons in annual methane emissions through syntrophic interactions. Previous work revealed how a sulfate reducer (Desulfovibrio vulgaris, Dv) and a methanogen (Methanococcus maripaludis, Mm) underwent evolutionary diversification in a planktonic context, improving stability, cooperativity, and productivity within 300-1000 generations. Here, we show that mutations in just 15 Dv and 7 Mm genes within a minimal assemblage of this evolved community gave rise to co-existing ecotypes that were spatially enriched within a few days of culturing in a fluidized bed reactor.

Disrupting the ArcA Regulatory Network Amplifies the Fitness Cost of Tetracycline Resistance in Escherichia coli.

There is an urgent need for strategies to discover secondary drugs to prevent or disrupt antimicrobial resistance (AMR), which is causing >700,000 deaths annually. Here, we demonstrate that tetracycline-resistant (Tet) Escherichia coli undergoes global transcriptional and metabolic remodeling, including downregulation of tricarboxylic acid cycle and disruption of redox homeostasis, to support consumption of the proton motive force for tetracycline efflux. Using a pooled genome-wide library of single-gene deletion strains, at least 308 genes, including four transcriptional regulators identified by our network analysis, were confirmed as essential for restoring the fitness of Tet E.

Reconsidering the in vivo functions of Clostridial Stickland amino acid fermentations.

Stickland amino acid fermentations occur primarily among species of Clostridia. An ancient form of metabolism, Stickland fermentations use amino acids as electron acceptors in the absence of stronger oxidizing agents and provide metabolic capabilities to support growth when other fermentable substrates, such as carbohydrates, are lacking. The reactions were originally described as paired fermentations of amino acid electron donors, such as the branched-chain amino acids, with recipients that include proline and glycine.

Transcriptome signature of cell viability predicts drug response and drug interaction in .

There is an urgent need for new drug regimens to rapidly cure tuberculosis. Here, we report the development of drug response assayer (DRonA) and "MLSynergy," algorithms to perform rapid drug response assays and predict response of (Mtb) to drug combinations. Using a transcriptome signature for cell viability, DRonA detects Mtb killing by diverse mechanisms in broth culture, macrophage infection, and patient sputum, providing an efficient and more sensitive alternative to time- and resource-intensive bacteriologic assays.

Quantitative prediction of conditional vulnerabilities in regulatory and metabolic networks using PRIME.

The ability of Mycobacterium tuberculosis (Mtb) to adopt heterogeneous physiological states underlies its success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why the tuberculosis (TB) mortality rate is so high, with over 1.8 million deaths annually.

In vivo commensal control of Clostridioides difficile virulence.

Leveraging systems biology approaches, we illustrate how metabolically distinct species of Clostridia protect against or worsen Clostridioides difficile infection in mice by modulating the pathogen's colonization, growth, and virulence to impact host survival. Gnotobiotic mice colonized with the amino acid fermenter Paraclostridium bifermentans survive infection with reduced disease severity, while mice colonized with the butyrate-producer, Clostridium sardiniense, succumb more rapidly. Systematic in vivo analyses revealed how each commensal alters the gut-nutrient environment to modulate the pathogen's metabolism, gene regulatory networks, and toxin production.

Predictive regulatory and metabolic network models for systems analysis of Clostridioides difficile.

We present predictive models for comprehensive systems analysis of Clostridioides difficile, the etiology of pseudomembranous colitis. By leveraging 151 published transcriptomes, we generated an EGRIN model that organizes 90% of C. difficile genes into a transcriptional regulatory network of 297 co-regulated modules, implicating genes in sporulation, carbohydrate transport, and metabolism.

History and Future Perspectives on the Discipline of Quantitative Systems Pharmacology Modeling and Its Applications.

Mathematical biology and pharmacology models have a long and rich history in the fields of medicine and physiology, impacting our understanding of disease mechanisms and the development of novel therapeutics. With an increased focus on the pharmacology application of system models and the advances in data science spanning mechanistic and empirical approaches, there is a significant opportunity and promise to leverage these advancements to enhance the development and application of the systems pharmacology field. In this paper, we will review milestones in the evolution of mathematical biology and pharmacology models, highlight some of the gaps and challenges in developing and applying systems pharmacology models, and provide a vision for an integrated strategy that leverages advances in adjacent fields to overcome these challenges.

Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells.

Metabolic reprogramming and its molecular underpinnings are critical to unravel the duality of cancer cell function and chemo-resistance. Here, we use a constraints-based integrated approach to delineate the interplay between metabolism and epigenetics, hardwired in the genome, to shape temozolomide (TMZ) resistance. Differential metabolism was identified in response to TMZ at varying concentrations in both the resistant neurospheroidal (NSP) and the susceptible (U87MG) glioblastoma cell-lines.

Integrated constraints based analysis of an engineered violacein pathway in Escherichia coli.

Strategies towards optimal violacein biosynthesis, a potential drug molecule, need systems level coordination of enzymatic activities of individual genes in a multigene operon vioABCDE. Constraints-based flux balance analysis of an extended iAF1260 model (iAF1260vio) with a reconstructed violacein module predicted growth and violacein yields in Escherichia coli accurately. Shadow price (SP) analysis identified tryptophan metabolism and NADPH as limiting.