We study the molecular mechanisms used by bacteria to display and utilize virulence factors. Our goal is to leverage this knowledge to discover novel antibiotics and to develop new tools for biotechnological applications. Our research is interdisciplinary, but primarily employs NMR, crystallography, biochemical and microbiological methods.


 

Ongoing Research

Structural Biology of Protein and Polymer Display

Bacterial pathogens display virulence factors that enable them to adhere to host tissues, resist phagocytic killing, invade host cells and acquire essential nutrients. We are studying how bacteria synthesize and display two types of virulence factors: (i) pili, proteinaceous fibers that project from the bacterial cell surface to mediate adhesion, and (ii) Wall Teichoic Acids (WTAs), highly...

Molecular Basis of Heme-Iron Acquisition by Pathogenic Microbes

To successfully mount infections bacterial pathogens actively procure iron from their human host, which is extremely scarce because of nutritional immunity mechanisms. Hemoglobin within erythrocytes is an attractive source of iron, as it contains ~75-80% of the body’s total iron in the form of heme (iron-protoporphyrin IX). In ongoing research, we studying the molecular mechanisms used by Gram...

Chemical Biology: Antibiotic Discovery

The emergence of antibiotic resistance bacteria is significant health concern. Our goal is to discover new anti-infective agents that can be used to combat infections caused by methicillin resistant Staphylococcus aureus (MRSA) and other multidrug resistant Gram-positive bacteria. Toward this objective, we are using high throughput screening approaches to identify small molecules that...

Recent Publications

McConnell SA, Amer BR, Muroski J, Fu J, Loo RO, Loo JA, Osipiuk J, Ton-That J and Clubb RT.  Protein labeling via a specific lysine-isopeptide bond using the pilin polymerizing sortase from Corynebacterium diphtheria. Journal of the American Chemical Society 2018 (in press)

Chang C, Amer BR, Osipiuk J, McConnell SA, Huang I-H, Hsieh V, Fu J, Nguyen HH, Muroski J, Flores E, Loo RO, Loo JA, Putkey JA, Joachimiak A, Das A, Clubb RT and Ton-That H. In vitro reconstitution of sortase-catalyzed pilus polymerization reveals structural elements involved in pilin crosslinking.  Proc Natl Acad Sci U S A. 2018 (in press)

Huang GL, Gosschalk JE, Kim YS and Clubb RT. Stabilizing displayed proteins on vegetative Bacillus subtilis cells. Appl Microbiol Biotechnol. 2018. doi:10.1007/s00253-018-9062-x

Sjodt M, Macdonald R, Marshall JD, et al. Energetics Underlying Hemin Extraction from Human Hemoglobin by Staphylococcus aureus. J Biol Chem. 2018. doi:10.1074/jbc.RA117.000803.

Jacobitz AW, Kattke MD, Wereszczynski J, Clubb RT. Sortase Transpeptidases: Structural Biology and Catalytic Mechanism. Adv Protein Chem Struct Biol. 2017;109. doi:10.1016/bs.apcsb.2017.04.008.

Chan AH, Yi SW, Weiner EM, et al. NMR structure-based optimization of Staphylococcus aureus sortase A pyridazinone inhibitors. Chem Biol Drug Des. 2017;90(3):327-344. doi:10.1111/cbdd.12962.

Kattke MD, Chan AH, Duong A, et al. Crystal Structure of the Streptomyces coelicolor Sortase E1 Transpeptidase Provides Insight into the Binding Mode of the Novel Class E Sorting Signal. Ton-That H, ed. PLoS ONE. 2016;11(12):e0167763. doi:10.1371/journal.pone.0167763.