An ensemble-guided approach identifies ClpP as a major regulator of transcript levels in nitric oxide-stressed Escherichia coli. Author Jonathan Robinson, Mark Brynildsen Publication Year 2015 Type Journal Article Abstract The importance of NO(∙) to immunity is highlighted by the diversity of pathogens that require NO(∙)-defensive systems to establish infections. Proteases have been identified to aid pathogens in surviving macrophage attack, inspiring us to investigate their role during NO(∙) stress in Escherichia coli. We discovered that the elimination of ClpP largely impaired NO(∙) detoxification by E. coli. Using a quantitative model of NO(∙) stress, we employed an ensemble-guided approach to identify the underlying mechanism. Iterations of in silico analyses and corresponding experiments identified the defect to result from deficient transcript levels of hmp, which encodes NO(∙) dioxygenase. Interestingly, the defect was not confined to hmp, as ΔclpP imparted widespread perturbations to the expression of NO(∙)-responsive genes. This work identified a target for anti-infective therapies based on disabling NO(∙) defenses, and demonstrated the utility of model-based approaches for exploring the complex, systems-level stress exerted by NO(∙). Keywords Stress, Physiological, Escherichia coli, Promoter Regions, Genetic, Sequence Analysis, RNA, Transcription, Genetic, RNA, Messenger, Escherichia coli Proteins, Biocatalysis, Dihydropteridine Reductase, Hemeproteins, NADH, NADPH Oxidoreductases, Nitric Oxide, Endopeptidase Clp Journal Metab Eng Volume 31 Pages 22-34 Date Published 2015 Sep ISSN Number 1096-7184 DOI 10.1016/j.ymben.2015.06.005 Alternate Journal Metab Eng PMID 26112956 PubMedGoogle ScholarBibTeXEndNote X3 XML