Locking the redox switch: a convergent target of adaptive mutations

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Microbes never fail to surprise us by showing how many different ways they can innovate to tackle environmental assault. Earlier this year a publication from our group in Nature Microbiology showed the peroxide sensor, OxyR, being mutated in an iron import deficient strain of Escherichia coli when grown in an iron-rich environment (Anand et al. 2019). This motivated us to identify the selection pressure targeting this gene and the adaptive consequences of these genetic changes on microbial physiology.

OxyR is a conserved transcriptional regulator in bacteria responsible for sensing peroxide and activating the gene network involved in the mitigation of oxidative stress caused by elevated levels of peroxide (Chiang and Schellhorn 2012). Iron overload can perturb the cellular redox homeostasis. This is due to the iron-dependent reaction, discovered by Henry John Fenton, which results in the generation of extremely reactive and damaging hydroxyl radicals upon reacting with hydrogen peroxide (Fenton 1894). We hypothesized that this toxic property of iron was the selection pressure on oxyR. We probed this theory by performing adaptive laboratory evolution of a wild type strain of E. coli in an iron-replete condition. It was gratifying to observe that every biologically independent replicate acquired a mutation in the oxyR gene. Further, a systems-level analysis explained the adaptive significance of the mutations. The mutations lock OxyR in its oxidized form, resulting in the constitutive activation of its gene regulatory network. This enabled higher peroxide tolerance and less DNA damage in the evolved strains.

A similar genetic change was observed during the adaptive laboratory evolution of Vibrio natriegens, which is one of the fastest-growing microbes and therefore has elevated aerobic metabolic flux (Lee et al., 2016; Panko 2016). Thus, multiple growth conditions percolating in similar cellular stress led microbes to identify a common adaptive feature. However, the constitutive activation of a gene regulatory network has its share of negative impact on the growth capacity of the organisms. We observed a ‘fear-greed’ tradeoff in the evolved strains. Last but certainly not least, we identified several natural isolates of E. coli with similar OxyR mutations indicating that conformational locking may be a widespread adaptive strategy of microbes.


Anand, Amitesh, Connor A. Olson, Laurence Yang, Anand V. Sastry, Edward Catoiu, Kumari Sonal Choudhary, Patrick V. Phaneuf, et al. 2019. “Pseudogene Repair Driven by Selection Pressure Applied in Experimental Evolution.” Nature Microbiology 4 (3): 386–89.

Chiang, Sarah M., and Herb E. Schellhorn. 2012. “Regulators of Oxidative Stress Response Genes in Escherichia Coli and Their Functional Conservation in Bacteria.” Archives of Biochemistry and Biophysics 525 (2): 161–69.

Fenton, H. J. H. 1894. “LXXIII.—Oxidation of Tartaric Acid in Presence of Iron.” J. Chem. Soc., Trans. https://doi.org/10.1039/ct8946500899.

Lee, Henry H., Nili Ostrov, Brandon G. Wong, Michaela A. Gold, Ahmad S. Khalil, and George M. Church. n.d. “Vibrio Natriegens, a New Genomic Powerhouse.” https://doi.org/10.1101/058487.

Panko, Ben. 2016. “Scientists Want to Replace Lab Workhorse E. Coli with the World’s Fastest-Growing Bacterium.” Science. https://doi.org/10.1126/science.aag0626.

Amitesh Anand

Postdoctoral Scholar, UCSD

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