Ensemble Modeling Identifies the Mechanism By Which Clpp Impacts NO• Defense Systems in E. coli
International Conference Biomolecular Engineering ICBE
2015
5th ICBE - International Conference on Biomolecular Engineering
Posters
Poster Session
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 infection1-7. 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• stress8,9 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
1 Kakishima, K., Shiratsuchi, A., Taoka, A., Nakanishi, Y. & Fukumori, Y. (2007), Participation of nitric oxide reductase in survival of Pseudomonas aeruginosa in LPS-activated macrophages, Biochem Biophys Res Commun, 355, 587-591.
2 Darwin, K. H., Ehrt, S., Gutierrez-Ramos, J. C., Weich, N. & Nathan, C. F. (2003), The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide, Science, 302, 1963-1966.
3 Kulasekara, B. R., Jacobs, M., Zhou, Y., Wu, Z., Sims, E., Saenphimmachak, C., Rohmer, L., Ritchie, J. M., Radey, M., McKevitt, M., Freeman, T. L., Hayden, H., Haugen, E., Gillett, W., Fong, C., Chang, J., Beskhlebnaya, V., Waldor, M. K., Samadpour, M., Whittam, T. S., Kaul, R., Brittnacher, M. & Miller, S. I. (2009), Analysis of the genome of the Escherichia coli O157:H7 2006 spinach-associated outbreak isolate indicates candidate genes that may enhance virulence, Infect Immun, 77, 3713-3721.
4 Shimizu, T., Tsutsuki, H., Matsumoto, A., Nakaya, H. & Noda, M. (2012), The nitric oxide reductase of enterohaemorrhagic Escherichia coli plays an important role for the survival within macrophages, Mol Microbiol, 85, 492-512.
5 Stern, A. M., Hay, A. J., Liu, Z., Desland, F. A., Zhang, J., Zhong, Z. & Zhu, J. (2012), The NorR regulon is critical for Vibrio cholerae resistance to nitric oxide and sustained colonization of the intestines, MBio, 3, e00013-00012.
6 Stevanin, T. M., Moir, J. W. & Read, R. C. (2005), Nitric oxide detoxification systems enhance survival of Neisseria meningitidis in human macrophages and in nasopharyngeal mucosa, Infect Immun, 73, 3322-3329.
7 Karlinsey, J. E., Bang, I. S., Becker, L. A., Frawley, E. R., Porwollik, S., Robbins, H. F., Thomas, V. C., Urbano, R., McClelland, M. & Fang, F. C. (2012), The NsrR regulon in nitrosative stress resistance of Salmonella enterica serovar Typhimurium, Mol Microbiol, 85, 1179-1193.
8 Robinson, J. L. & Brynildsen, M. P. (2013), A kinetic platform to determine the fate of nitric oxide in Escherichia coli, PLoS computational biology, 9, e1003049.
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.