Clubb, Robert T.

Short Biography

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).

Research Interests

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 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.

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-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.

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 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.