Oxidative stress has been linked to a variety of human pathologies. It is also critical to bacterial pathogenesis, both because oxygen limits the virulence of microaerophiles and because macrophages use oxidants to attack bacterial invaders. Therefore it is important to achieve a molecular understanding to the mechanisms by which oxygen species damage cells and to the tactics that cells employ to defend themselves. The long-term goal of our lab is to resolve these issues using model bacteria as study subjects. Our current aims are: (1) To explore the molecular basis of the oxygen intolerance of Bacteroides thetaiotaomicron. Preliminary data suggest that B. theta is consigned to anaerobiosis in part because its fumarase, a key iron- sulfur dehydratase, loses activity in air. If this idea is confirmed, then a second problem will be explored: Why does air inactivate such iron-sulfur clusters in B. theta but not in E. coli? (2) To explain unsolved phenotypes of superoxide dismutase-deficient E. coli. SOD mutants cannot synthesize branched-chain amino acids or catabolize non-fermentable carbon sources, and they suffer rapid mutagenesis. These traits have been clearly explained by iron-sulfur cluster damaged. However, these mutants also require reduced sulfur and aromatic amino acids. Circumstantial evidence suggests that these phenotypes, too, evolve from cluster damage. (3) To explain why E. coli synthesizes two aconitases. During oxidative stress E. Coli induces a superoxide-resistant isozyme to replace the labile one. This begs the question: Why maintain a labile isozyme at all? One answer may be trivial--that the primary aconitase is kinetically superior--but a more interesting possibility is that the inactivation of the major aconitase is beneficial during periods of iron starvation. (4) To uncover the mechanisms by which the SoxRS regulon defends oxidatively stressed cells. The SoxRS regulon induces several enzymes that provide obvious benefits to superoxide-stressed cells, but the purposes of others are more obscure. It is plausible that some of the latter enzymes help to repair damaged iron-sulfur clusters. Other, such as glucose-6-phosphate dehydrogenases, may be understandable only if some of the toxicity of these drugs arises from NADPH depletion rather than from reactive oxygen species.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Microbial Physiology and Genetics Subcommittee 2 (MBC)
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Ikeda, Richard A
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University of Illinois Urbana-Champaign
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Lu, Zheng; Sethu, Ramakrishnan; Imlay, James A (2018) Endogenous superoxide is a key effector of the oxygen sensitivity of a model obligate anaerobe. Proc Natl Acad Sci U S A 115:E3266-E3275
Li, Xin; Imlay, James A (2018) Improved measurements of scant hydrogen peroxide enable experiments that define its threshold of toxicity for Escherichia coli. Free Radic Biol Med 120:217-227
Khademian, Maryam; Imlay, James A (2017) Escherichia coli cytochrome c peroxidase is a respiratory oxidase that enables the use of hydrogen peroxide as a terminal electron acceptor. Proc Natl Acad Sci U S A 114:E6922-E6931
Lu, Zheng; Imlay, James A (2017) The Fumarate Reductase of Bacteroides thetaiotaomicron, unlike That of Escherichia coli, Is Configured so that It Does Not Generate Reactive Oxygen Species. MBio 8:
Imlay, James A (2015) Transcription Factors That Defend Bacteria Against Reactive Oxygen Species. Annu Rev Microbiol 69:93-108
Mancini, Stefano; Imlay, James A (2015) Bacterial Porphyrin Extraction and Quantification by LC/MS/MS Analysis. Bio Protoc 5:
Mancini, Stefano; Imlay, James A (2015) The induction of two biosynthetic enzymes helps Escherichia coli sustain heme synthesis and activate catalase during hydrogen peroxide stress. Mol Microbiol 96:744-63
Imlay, James A (2015) Diagnosing oxidative stress in bacteria: not as easy as you might think. Curr Opin Microbiol 24:124-31
Imlay, James A (2014) The mismetallation of enzymes during oxidative stress. J Biol Chem 289:28121-8
Sobota, Jason M; Gu, Mianzhi; Imlay, James A (2014) Intracellular hydrogen peroxide and superoxide poison 3-deoxy-D-arabinoheptulosonate 7-phosphate synthase, the first committed enzyme in the aromatic biosynthetic pathway of Escherichia coli. J Bacteriol 196:1980-91

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