Bacillithiol and the Redox Biology of Bacillus Subtilis

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This project is exploring the biological mechanisms that allow cells to protect cytosolic proteins against chemical modification. These biological mechanisms are critical for cells to avoid damage, for example, due to oxidative stress or exposure to toxic heavy metals. Cytosolic proteins often contain reduced cysteine residues which contain a thiol functional group (RSH). Such groups are susceptible to modification by reactive oxygen and nitrogen species, electrophiles, and toxic metals and metalloids. Cells contain abundant, low molecular mass thiol compounds that serve to buffer the harmful impact of these reactive chemicals and may also participate in the repair of damaged proteins. In many cells, this role is played by glutathione (GSH), a cysteine-containing tripeptide. Many Gram positive bacteria (phylum Firmicutes) lack GSH and this protective role is assumed by bacillithiol (BSH), a recently characterized compound containing cysteine, glucosamine, and malic acid. This research explores the diverse roles of BSH in the model organism Bacillus subtilis. The role of BSH in protection against reactive oxygen compounds (including peroxides and hypochlorous acid), electrophiles (methylglyoxal, formaldehyde), and toxic metalloids are being investigated using genetic, physiological, and biochemical methods. BSH is a required co-substrate for some detoxification enzymes and differs from GSH in its chemical properties and affinity for metal ions. The presence of BSH in diverse bacteria argues that the paradigms established by a detailed characterization of this novel thiol are having far-reaching implications. Broader impacts This project involves a combination of biochemical, genetic, genomic, and physiological approaches. The results will have general implications for biological systems including those pertaining to medical and agriculture problems. The experimental work is conducted by undergraduate, graduate, and post-doctoral students who will receive broad training in multidisciplinary approaches to investigating bacterial physiology. Students employ state-of-the-art transcriptional profiling, proteomics, chemical and biophysical techniques and gain experience in analyzing and interpreting the resulting data. Students at all levels present their work locally during group meetings and in department seminars and at regional, national, and international conferences as either posters or oral presentations. Students prepare drafts of manuscripts and are involved in all stages of the publishing process. In addition, students are being expected to be active as mentors to new members of the laboratory. Finally, students have the opportunity to interact with collaborating laboratories with similar research interests and learn about ongoing, complementary projects in related organisms. Previous students who have worked on this project have gone on to successful careers in academics and industry.