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Professor Liem Nguyen
Case Western Reserve University School of Medicine, U.S.A.
Title of the talk: A Metabolic Trap Promotes Bacterial Thymineless Death by Sulfa Drugs
The methylfolate trap is a metabolic defect causing human diseases such as anemia, neural tube defects, cardiovascular diseases, Alzheimer’s dementia, cancer, and others. Discovered in 1962, the methylfolate trap has been known to interconnect multiple metabolic pathways including folate, vitamin B12, methionine and homocysteine in mammalian cells. However, the existence and physiological significance of this phenomenon has remained unknown in bacteria, which synthesize folate de novo. Using a chemo-genomic approach, we uncovered the methylfolate trap as a novel determinant of the bacterial intrinsic death by sulfonamides (sulfa drugs), antibiotics that block the de novo folate synthesis. Metabolomic profiling, in combination with genetic mutagenesis and exogenous chemical complementation, revealed trap-mediated metabolic imbalances causing thymineless death, a form of bacterial programmed cell death resulted from thymine starvation. Chemical depletion of vitamin B12, required for preventing the methylfolate trap formation, by using an “anti-B12” molecule, sensitized intracellular bacteria to the killing by sulfonamides. Because the promotion of sulfonamides’ potency through inducing the methylfolate trap is achievable against pathogenic mycobacteria and Gram-negative bacteria, it represents a novel folate antagonistic strategy that may render drug resistant pathogens more susceptible to existing sulfonamides.
Liem Nguyen is an Associate Professor at the Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine in Cleveland, Ohio, USA. He obtained his Ph.D. in Microbiology from the Czech Academy of Sciences in Prague, Czech Republic in 2001. After graduation, he trained as a postdoctoral fellow at the Biozentrum, University of Basel in Switzerland where he studied the molecular biology of antibiotic resistance and virulence mechanisms in pathogenic mycobacteria. In 2004, he joined the faculty of the Department of Microbiology and Immunology, University of British Columbia, Canada, where he expanded his research to the cell biology and pathogenesis of Mycobacterium tuberculosis. Dr. Nguyen was recruited in 2006 to the Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, in Cleveland, Ohio, where he has been directing a laboratory studying on molecular mechanisms of drug resistance and virulence factors of Mycobacterium tuberculosis. He is the recipient of several awards including the 4th Annual Swiss TB Award (2005), the STERIS Infectious Diseases Research Awards (2007, 2011) and the CFAR Developmental Awards (2007, 2009). Work in Nguyen’s laboratory are supported by the US National Institutes of Health.