@article { ISI:000282259600001,
	title = {Systems approach to investigating host-pathogen interactions in infections with the biothreat agent Francisella. constraints-based model of Francisella tularensis},
	journal = {BMC Systems Biology},
	volume = {4},
	year = {2010},
	month = {AUG},
	pages = {118},
	publisher = {BIOMED CENTRAL LTD},
	address = {236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND},
	abstract = {<p>Background: Francisella tularensis is a prototypic example of a pathogen for which few experimental datasets exist, but for which copious high-throughout data are becoming available because of its re-emerging significance as biothreat agent. The virulence of Francisella tularensis depends on its growth capabilities within a defined environmental niche of the host cell. Results: We reconstructed the metabolism of Francisella as a stoichiometric matrix. This systems biology approach demonstrated that changes in carbohydrate utilization and amino acid metabolism play a pivotal role in growth, acid resistance, and energy homeostasis during infection with Francisella. We also show how varying the expression of certain metabolic genes in different environments efficiently controls the metabolic capacity of F. tularensis. Selective gene-expression analysis showed modulation of sugar catabolism by switching from oxidative metabolism (TCA cycle) in the initial stages of infection to fatty acid oxidation and gluconeogenesis later on. Computational analysis with constraints derived from experimental data revealed a limited set of metabolic genes that are operational during infection. Conclusions: This integrated systems approach provides an important tool to understand the pathogenesis of an ill-characterized biothreat agent and to identify potential novel drug targets when rapid target identification is required should such microbes be intentionally released or become epidemic.</p>},
	issn = {1752-0509},
	doi = {10.1186/1752-0509-4-118},
	author = {Raghunathan, Anu and Shin, Sookil and Daefler, Simon}
}
@article {43934,
	title = {Scalable metabolite supplementation strategy against antibiotic resistant pathogen Chromobacterium violaceum induced by NAD(+)/NADH(+) imbalanceA scalable metabolite supplementation strategy against antibiotic resistant pathogen Chromobacterium violaceu},
	journal = {BMC Syst Biol. },
	volume = {11},
	year = {2017},
	month = {APR},
	abstract = {<p>BACKGROUND: The leading edge of the global problem of antibiotic resistance necessitates novel therapeutic strategies. This study develops a novel systems biology driven approach for killing antibiotic resistant pathogens using benign metabolites. RESULTS: Controlled laboratory evolutions established chloramphenicol and streptomycin resistant pathogens of Chromobacterium. These resistant pathogens showed higher growth rates and required higher lethal doses of antibiotic. Growth and viability testing identified malate, maleate, succinate, pyruvate and oxoadipate as resensitising agents for antibiotic therapy. Resistant genes were catalogued through whole genome sequencing. Intracellular metabolomic profiling identified violacein as a potential biomarker for resistance. The temporal variance of metabolites captured the linearized dynamics around the steady state and correlated to growth rate. A constraints-based flux balance model of the core metabolism was used to predict the metabolic basis of antibiotic susceptibility and resistance. CONCLUSIONS: The model predicts electron imbalance and skewed NAD/NADH ratios as a result of antibiotics - chloramphenicol and streptomycin. The resistant pathogen rewired its metabolic networks to compensate for disruption of redox homeostasis. We foresee the utility of such scalable workflows in identifying metabolites for clinical isolates as inevitable solutions to mitigate antibiotic resistance.</p>},
	keywords = {Antibiotic resistance; Flux balance analysis; Flux variability analysis; Metabolism; Metabolomic; NAD; NADH; Redox homeostasis},
	doi = {10.1186/s12918-017-0427-z},
	author = {Banerjee, Deepanwita and Parmar, Dharmeshkumar and Bhattacharya, Nivedita and Ghanate, Avinash D. and Panchagnula, Venkateswarlu and Raghunathan, Anu}
}
