Ensemble Modeling Identifies the Mechanism By Which Clpp Impacts NO• Defense Systems in E. coli

Nitric oxide (NO•) is an antimicrobial used by immune cells to neutralize pathogens. The importance of NO• to immune function is evidenced by the many pathogens, including Mycobacterium tuberculosis, Neisseria meningitides, Vibrio cholerae, Salmonella enterica, and enterohemorrhagic Escherichia coli (EHEC), that depend on NO• detoxification to establish an infection^1-7.  Inhibitors of NO• defense systems have the potential to form a novel class of anti-infectives; however, known agents are either toxic to humans or poorly transported into bacterial cells. Here I will discuss our discovery of ClpP as major mediator of NO• stress in E. coli, and how we used a quantitative model of NO• stress^8,9 within an innovative ensemble approach to elucidate the underlying mechanism. These results demonstrate the utility of quantitative modeling to the study of complex, systems-level stresses, such as NO•, and identify a novel target that when inhibited enhances the antimicrobial effects of NO• on E. coli.

References

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9          Robinson, J. L., Miller, R. V. & Brynildsen, M. P. (2014), Model-Driven Identification of Dosing Regimens that Maximize the Antimicrobial Activity of Nitric Oxide, Metabolic Engineering Communications, accepted.