Susan M. Egan
Ph.D., Cornell University, 1991
8031 Haworth; Phone: (785) 864-4294, e-mail:
My primary research interest is understanding the regulation of gene expression (especially positive regulation) at a molecular level. In our lab we examine the molecular biology of gene regulation in E. coli, with a focus on the L-rhamnose catabolic genes, and the fact that the L-rhamnose regulator genes are members of the AraC family of regulatory proteins. Many AraC family proteins are regulators of virulence factors in bacterial pathogens, therefore, we use the L-rhamnose regulators as models to understand the function of proteins in this family. Our ultimate goal is to identify small molecules that block the function of AraC family proteins and have potential as anti-bacterial agents.
The widespread availability of antibiotics since the 1940’s has dramatically reduced the number of deaths due to bacterial infections, however we are rapidly losing our advantage over our bacterial foes as antibiotic resistance becomes increasingly prevalent. We must investigate novel targets for antibacterial agents to avoid the return of commonplace deaths due to bacterial infections. Many members of the very large AraC/XylS family of transcription activators are required for the expression of virulence factors in bacterial pathogens. In several cases it has been shown that deletion of an AraC/XylS activator drastically reduces pathogenesis, indicating that members of this family have potential as targets for antibacterial agents. Our long-term goal is to identify small molecule inhibitors of AraC/XylS family activators. Towards this goal, we are currently working on two fronts. First, we are performing a screen of a large library of small molecules for ones that specifically inhibit the activity of the AraC/XylS family protein RhaS. Once we identify compounds that are inhibitory, we will investigate their mechanism of action. Towards this end, we are also investigating the mechanisms used by the AraC/XylS family protein RhaS that underlie its ability to activate transcription of the appropriate genes and under the appropriate conditions. Once we have identified the mechanisms of a few more of RhaS’s functions, we will be in an excellent position to identify the mechanisms of action of inhibitory small molecules. Ultimately, we will screen for inhibitors of AraC/XylS family activators of virulence factors in bacterial pathogens. We expect that these inhibitors have potential to be developed into novel strategies for treatment of bacterial diseases.
We have already obtained a substantial amount of information about RhaS function. For example, we have identified four amino acid residues in RhaS that make base-specific contacts with its DNA-binding site, and further, have identified the base-pairs in the DNA that each of these residues contacts. This allows us to unequivocally orient each monomer of the RhaS dimer on its DNA site. We have also identified two amino acid residues in RhaS that are directly required to contact RNA polymerase to activate transcription. In addition, we have identified the amino acid residues in the sigma70 subunit of RNA polymerase that each of these RhaS residues contacts. There are only very few transcription activators for which interactions with RNA polymerase have been defined at this level of detail. We are currently investigating the mechanisms by which RhaS: dimerizes; binds its ligand, L-rhamnose; and transmits the information that L-rhamnose is or is not available from its N-terminal ligand binding and dimerization domain to its C-terminal DNA-binding and transcription activation domain.
Current Graduate Students
Bria Wilkins Kettle
Wickstrum, J. R., J. M. Skredenske, V. Balasubramaniam, K. Jones and S. M. Egan. 2010. The AraC/XylS Family Activator RhaS Negatively AutoregulatesrhaSR Expression by Preventing Cyclic AMP Receptor Protein Activation. Journal of Bacteriology. 192(1):225-32. Find Article Online.
Kolin, A., V. Balasubramaniam, J. M. Skredenske, J. R. Wickstrum and S. M. Egan. 2008. Differences in the Mechanism of the Allosteric L-Rhamnose Responses of the AraC/XylS Family Transcription Activators RhaS and RhaR. Molecular Microbiology. 68(2):448–461. Find Article Online.
Wickstrum, J. R., J. M. Skredenske, A., Kolin, D. J., Jin, J. Fang and S. M. Egan. 2007. Transcription Activation by the DNA-Binding Domain of the AraC Family Protein RhaS in the Absence of its Effector-Binding Domain. Journal of Bacteriology. 189(14):4984–93. Find Article Online.
Tungtur, S., S. M. Egan and L. Swint-Kruse. 2007. Functional consequences of exchanging domains between LacI and PurR are mediated by the intervening linker sequence. Proteins: Structure, Function, and Bioinformatics. 68(1):375–88. Find Article Online.
Kolin, A., V. Jevtic, L. Swint-Kruse and S. M. Egan. 2007. Linker regions of the RhaS and RhaR proteins. Journal of Bacteriology. 189(1):269–71. Find Article Online.
Wickstrum, J. R., T. J. Santangelo and S. M. Egan. 2005. Cyclic AMP receptor protein and RhaR synergistically activate transcription from the L-Rhamnose-responsive rhaSR promoter in Escherichia coli. Journal of Bacteriology. 187(19):6708–6718. Find Article Online.
Wickstrum, J. R. and S. M. Egan. 2004. Amino acid contacts between Sigma 70 domain 4 and the transcription activators RhaS and RhaR. Journal of Bacteriology. 186(18):6277–6285. Find Article Online.
Egan, S. M. 2002. Growing Repertoire of AraC/XylS Activators. J. Bacteriol. 184(20):5529–5532. Find Article Online.
Wickstrum, J. R. and S. M. Egan. 2002. Ni+-affinity purification of untagged cyclic AMP receptor protein. BioTechniques 33(4):728–730. (Featured in “BioSpotlight,” p. 713).
Ruiz R., J. L. Ramos and S. M. Egan. 2001. Interactions of the XylS regulators with the C-terminal domain of the RNA polymerase alha subunit influence the expression level from the cognate Pm promoter. FEBS Letters. 491:207–211. Find Article Online.
Egan, S. M., A. J. Pease, J. Lang, X. Li, V. Rao, W. K. Gillette, R. Ruiz, J. L. Ramos, and R. E. Wolf, Jr. 2000. Transcription activation by a variety of AraC/XylS family activators does not depend on the class-II-specific activation determinant in the N-terminal domain of the RNA polymerase alpha subunit. J. Bacteriol. 182(24):7075–7077. Find Article Online.
Holcroft, C. C., and S. M. Egan. 2000. Interdependence of activation at rhaSR by cyclic AMP receptor protein, the RNA polymerase alpha subunit C-terminal domain and RhaR. J. Bacteriol. 182(23):6774–6782. Find Article Online.
Bhende, P. M., and S. M. Egan. 2000. Genetic evidence that transcription activation by RhaS involves specific amino acid contacts with sigma 70. J. Bacteriol 182:4959–4969. Find Article Online.
Holcroft, C. C., and S. M. Egan. 2000. Roles of cyclic AMP receptor protein and the carboxyl-terminal domain of the a subunit in transcription activation of the Escherichia coli rhaBAD operon. J. Bacteriol. 182:3529–3535. Find Article Online.
Bhende, P. M. and S. M. Egan (1999). Amino acid-DNA contacts by RhaS: An AraC family transcription activator. J. Bacteriol. 181:5185–5192. Find Article Online.
Egan, S. M. & Schleif, R. F. (1994). DNA-dependent renaturation of an insoluble DNA binding protein: Identification of the RhaS binding site at rhaBAD. J. Mol. Biol. 243: 821–829. Find Article Online.
Egan, S. M. & Schleif, R. F. (1993). A regulatory cascade in the induction of rhaBAD. J. Mol. Biol. 234: 87–98. Find Article Online.
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