Project Description
We have identified multiple new "drug targets" within the structure of bacterial RNA polymerase, the enzyme that mediates bacterial gene expression. Each of these new targets can serve as a binding site for compounds that inhibit bacterial gene expression and thereby kill bacteria. For each of these new targets, we have identified at least one compound that binds to the new target and have characterized the activity of the compound. Several of the compounds exhibit high promise, exhibiting either potent anti-tuberculosis activity or potent broad spectrum antibacterial activity, and exhibiting no cross resistance with current anti-tuberculosis drugs and broad-spectrum antibacterial drugs.
Undergraduate projects will focus on (1) identification and characterization of new targets, (2) identification and characterization of new compounds, and/or (3) synthesis and characterization of optimized compounds.
Qualifications
GPA >=3.7 required.
Major in chemistry or molecular biology required.
Prior research experience in synthetic organic chemistry or molecular biology desirable.
Applications through Aresty Research Program preferred.
Publications with Undergraduate Co-authors
Niu, W., Kim, Y., Tau, G., Heyduk, and Ebright, R. (1996) Transcription activation at Class II CAP dependent promoters: two interactions between CAP and RNA polymerase. Cell 87, 1123 1134.
Parkinson, G., Wilson, C., Gunasekera, A., Ebright, Y., Ebright, R. and Berman, H. (1996) Structure of the CAP-DNA complex at 2.5 Å resolution: a complete picture of the protein-DNA interface. J. Mol. Biol. 260, 395-408.
Bayro, M., Mukhopadhyay, J., Swapna, G.V.T., Huang, J., Ma, L.-C., Sineva, E., Dawson, P., Montelione, G., and Ebright, R. (2003) Structure of antibacterial peptide microcin J25: a 21-residue lariat protoknot. J. Amer. Chem. Soc. 125, 12382 12383.
Srivastava, A., Talaue, M., Liu, S., Degen, D., Ebright, R.Y., Sineva, E., Chakraborty, A., Druzhinin, S., Chatterjee, S., Mukhopadhyay, J., Ebright, Y., Zozula, A., Shen, J., Sengupta, S., Niedfeldt, R., Xin, C., Kaneko, T., Irschik, H., Jansen, R., Donadio, S., Connell, N., and Ebright, R. (2011) New target for inhibition of bacterial RNA polymerase: "switch region." Curr. Opin. Microbiol. 14, 532-543.
Degen, D., Feng, Y., Zhang, Y., Ebright, K., Ebright, Y., Gigliotti, M., Vahedian-Movahed, H., Mandal, S., Talaue, M., Connell, N., Arnold, E., Fenical, W., and Ebright, R. (2014) Transcription inhibition by the depsipeptide antibiotic salinamide A. eLife, 3, e02451.
Feng, Y., Degen, D., Wang, X., Gigliotti, M., Liu, S., Zhang, Y., Das, D., Michalchuk, T., Ebright, Y., Talaue, M., Connell, N., and Ebright, R. (2015) Structural basis of transcription inhibition by CBR hydroxamidines and CBR pyrazoles. Structure 23, 1470-1481.
Lin, W., Mandal, S., Degen, D., Liu, Y.., Ebright, Y., Li, S., Feng, Y., Zhang, Y., Mandal, S., Jiang, Y., Liu, S., Gigliotti, M., Talaue, M., Connell, N., Das, K., Arnold, E., and Ebright, R. (2017) Structural basis of Mycobacterium tuberculosis transcription and transcription inhibition. Mol. Cell 166, 169-179.
Lin, W., Das, K., Degen, D., Mazumder, A., Duchi, D., Wang, D., Ebright, Y., Ebright, R.Y., Sineva, E., Gigliotti, M., Mandal, S., Jiang, Y., Liu, Y., Yin, R., Zhang, Z., Eng, E., Thomas, D., Donadio, S., Zhang, C., Kapanidis, A., and Ebright, R. (2018) Structural basis of transcription inhibition by fidaxomicin (lipiarmycin A3). Mol. Cell 70, 60-71.
Lin, W., Mandal, S., Degen, D., Cho, M., Feng, Y., Das, K., and Ebright, R.H. (2019) Structural basis of ECF-sigma-factor-dependent transcription initiation. Nature Commun. 10, 710.
