Keywords
1. Bacterial detoxification mechanisms
2. Hydrogen peroxide stress response
3. Nitric oxide bacterial resistance
4. Escherichia coli oxidative stress
5. Gene regulation oxidative stress
New research published in the Journal of Bacteriology, DOI: 10.1128/JB.00081-19, conducted by Kristin J. Adolfsen, Wen Kang Chou, and Mark P. Brynildsen from the Department of Chemical and Biological Engineering at Princeton University, has provided unprecedented insights into the bacterial prioritization of detoxifying agents. The paper, titled “Transcriptional Regulation Contributes to Prioritized Detoxification of Hydrogen Peroxide over Nitric Oxide,” reveals how the model organism Escherichia coli responds to oxidative stress by prioritizing the detoxification of hydrogen peroxide (H₂O₂) over nitric oxide (NO).
The study is significant as it sheds light on the survival strategies of bacteria in hostile environments, which is critical for developing new antimicrobial strategies. This research finding has profound implications for both microbiology and the medical field, especially in understanding how pathogenic bacteria withstand the immune system’s onslaught and how to potentially circumvent bacterial defenses.
The study addresses the complex interaction of gene expression and enzymatic regulation when E. coli cells face concurrent exposure to both NO and H₂O₂, two potent antimicrobial molecules produced by the human immune system. Previous research has indicated that E. coli uses numerous enzymes to break down H₂O₂, with alkyl hydroperoxide reductase being the primary scavenger (Seaver & Imlay, 2001). At the same time, nitric oxide is dealt with by a different set of enzymes, including the nitric oxide dioxygenase function of flavohemoglobin (Gardner et al., 1998).
The study employed multiple research methodologies, including genetic assays, transcriptional profiling, and enzymatic activity analyses. The results revealed that when faced with NO and H₂O₂, E. coli preferentially responds to H₂O₂ stress by elevating the expression of the hmp gene, which encodes flavohemoglobin responsible for NO detoxification. The transcriptional response indicates that the regulation of the scavenging components is hierarchical, prioritizing H₂O₂ detoxification.
One of the mechanisms unveiled through this study includes the identification of various regulatory proteins, such as OxyR and Fnr, which sense the oxidative and nitrosative stresses, respectively, and modulate the transcription of defense genes (D’Autréaux & Touati, 2002; Cruz-Ramos et al., 2002).
In the department’s press release, Brynildsen, the senior author, stated, “Our findings have revealed a nuanced strategy that bacteria use to handle chemical threats. The hierarchical approach to defensive measures suggests a cost-effective bacterial tactic, prioritizing resources to subdue the more dominant threat.”
The research was supported by federal grants (Research Support, Non-U.S. Gov’t and Research Support, U.S. Gov’t, Non-P.H.S.), emphasizing the national interest in deciphering microbial defense mechanisms against host-induced stresses.
These findings resonate with earlier work that has explored the complexity of how bacteria cope with multi-stress environments and the role of small regulatory RNAs and sigma factors in such conditions (Almeida et al., 2007; Shimizu et al., 2012). The current study furthers this understanding by elucidating that E. coli dynamically adjusts its transcriptional machinery in response to the qualitative nature of the encountered stress.
The importance of this research lies in its potential to aid in designing targeted antimicrobial treatments. By understanding the hierarchy in E. coli’s stress responses, therapeutic approaches can be developed to either overwhelm the bacteria’s defense systems or to manipulate them for improved pathogen clearance. The study serves as a cornerstone, encouraging further exploration into the selective pressures governing bacterial survival in vivo and the development of antibiotic resistance.
Future research in this domain could expand on how various bacterial strains with differing metabolic profiles handle the prioritization of stress defenses. It could also benefit from examining clinical isolates from infections to identify potential differences in stress response regulation that may contribute to pathogenicity or antibiotic resistance.
To conclude, Adolfsen, Chou, and Brynildsen’s research marks a step forward in our comprehension of bacterial physiology and the management of oxidative stress. While E. coli navigates through a chemical battlefield within the host, it carefully allocates its resources, displaying a sophisticated mechanism for maintaining cellular integrity and life amidst a continuous assault from the immune system.
The study is not only a testament to the intricate world of microbial gene regulation but also a guiding light for future research and treatment strategies against bacterial threats.
References
1. Adolfsen, K. J., Chou, W. K., & Brynildsen, M. P. (2019). Transcriptional Regulation Contributes to Prioritized Detoxification of Hydrogen Peroxide over Nitric Oxide. Journal of Bacteriology, 201(14), e00081-19. DOI:10.1128/JB.00081-19
2. Seaver, L. C., & Imlay, J. A. (2001). Alkyl hydroperoxide reductase is the primary scavenger of endogenous hydrogen peroxide in Escherichia coli. Journal of Bacteriology, 183(24), 7173-7181. DOI:10.1128/JB.183.24.7173-7181.2001
3. Gardner, P. R., Gardner, A. M., Martin, L. A., & Salzman, A. L. (1998). Nitric oxide dioxygenase: an enzymic function for flavohemoglobin. Proceedings of the National Academy of Sciences of the USA, 95(18), 10378–10383. DOI:10.1073/pnas.95.18.10378
4. D’Autréaux, B., & Touati, D. (2002). Direct inhibition by nitric oxide of the transcriptional ferric uptake regulation protein via nitrosylation of the iron. Proceedings of the National Academy of Sciences of the USA, 99(24), 16619-16624. DOI:10.1073/pnas.252591299
5. Cruz-Ramos, H., Crack, J., Wu, G., Hughes, M. N., Scott, C., Thomson, A. J., Green, J., & Poole, R. K. (2002). NO sensing by FNR: regulation of the Escherichia coli NO-detoxifying flavohaemoglobin, Hmp. EMBO Journal, 21(13), 3235-3244. DOI:10.1093/emboj/cdf339
6. Almeida, J. R., Modig, T., Petersson, A., Hähn-Hägerdal, B., Lidén, G., & Gorwa-Grauslund, M. F. (2007). Increased tolerance and conversion of inhibitors in lignocellulosic hydrolysates by Saccharomyces cerevisiae. Journal of Chemical Technology & Biotechnology, 82(4), 340-349. DOI:10.1002/jctb.1676
7. 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. Molecular Microbiology, 85(3), 492-512. DOI:10.1111/j.1365-2958.2012.08122.x