Clubb is a professor of chemistry, biochemistry, and molecular biology at UCLA. He is the lab director of the Clubb Lab and co-director and staff researcher at the Nuclear Magnetic Resonance (NMR) Core Technology Center (DOE).
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 abundant cell wall anionic glycopolymers that regulate cell division, and other fundamental aspects of bacterial physiology. A greater understanding of these processes could lead to new antibiotics to treat infections caused by multi-drug resistant bacteria.
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-positive bacteria to remove hemoglobin’s heme molecule, the first step gaining access to this rich nutrient source. In collaborative studies we are applying computational and experimental methodologies to decipher the structural, dynamic and energetic basis through which the S. aureus IsdH protein extracts heme from human hemoglobin (Hb). This process is highly conserved and used by many bacterial species to obtain the essential nutrient iron. Recent structural data and newly developed experimental tools make IsdH a powerful model system in which to explore the heme extraction mechanism.
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 prevent bacteria from displaying virulence factors. Our research is a collaborative effort with Mike Jung and Hung Ton-That’s research groups at UCLA, and employs computational, structural and synthetic chemistry methods to guide inhibitor optimization. Much of our effort has concentrated on discovering small molecules that inhibit the S. aureus Sortase A (SrtA) enzyme, as they could function as powerful anti-infective agents that work by preventing the display of protein virulence factors. At present, we are exploiting the recently discovered growth dependence of Actinomyces oris on the activity of its SrtA enzyme, which enables the application of powerful cell-based screening methods to identify inhibitors that may have novel molecular scaffolds that are uniquely suited for traversing the cell wall. Our current inhibitor research is also targeting the wall teichoic acid (WTA) biosynthetic pathway, as this highly abundant anionic glycopolymer has critical functions in cell division, morphology, adhesion, and microbial susceptibility to the immune response. The WTA biosynthetic pathway in S. aureus has drawn significant interest as a drug target, as clinically important MRSA strains that lack WTA are defective in host colonization and re-sensitized to beta-lactam antibiotics.
Below is the list of the most recent publications. For the full list, please visit here.
115. Clayton J, Ellis-Guardiola K, Mahoney B, Soule J, Clubb RT and Wereszczynski J. Directed inter-domain motions enable the IsdH Staphylococcus aureus receptor to rapidly extract heme from human hemoglobin. (accepted at JMB)
113. Martinez OE, Mahoney BJ, Goring AK, Yi SW, Tran DP, Cascio D, Phillips ML, Muthana MM, Chen X, Jung ME, Loo JA and Clubb RT. Insight into the molecular basis of substrate recognition by the wall teichoic acid glycosyltransferase TagA. Journal of Biological Chemistry 298 2022; 101464.
111. McConnell SA, McAllister RA, Amer BR, Mahoney B, Sue CK, Chang C, Ton-That H. and Clubb RT. Sortase-assembled pili in Corynebacterium diphtheriae are built using a latch mechanism. Proceedings of the National Academy of Sciences (USA) 118 2021; e2019649118
110. Ellis-Guardiola K, Mahoney B and Clubb RT. NEAr Transporter (NEAT) domains: novel surface displayed heme chaperones that enable Gram-positive bacteria to capture heme-iron from hemoglobin. Frontiers in Microbiology 11 2021; 607679