Transcript Natural products and their biological targets

Department of Chemistry
Seminar Announcement
Date/Time/Venue
Title/Speaker
21 Feb (Mon)
4pm – 5pm
Natural products and their biological targets
@ S8 Level 3
Executive
Classroom
Professor Stephan A Sieber
Technical University München, Germany
Host : Asst Prof Zeng Huaqiang
About the Speaker
Professor Stephan A Sieber received his Ph.D. in 2004 from Philipps-University
Marburg, Germany and continued to carry out his postdoctoral research with Prof
Benjamin F Cravatt at the Scripps Research Institute in La Lolla, USA in the same year.
In 2006, he started his independent research position at the University of Munich
(LMU) Germany, funded by a DFG Emmy Noether Fellowship.
Professor Sieber was appointed as a full Professor in 2009 at TUM. He is also the
Chair of Organic Chemistry II for the Department of Chemistry, TUM and is a member
of the Excellence Cluster "Center for Integrated Protein Science Munich” (CIPSM). His
research addresses complex biological questions by utilizing synthetic chemistry,
functional proteomics, cell biology and mass spectrometry techniques which represent a powerful
combination of methods for understanding the many facets of the molecular origins of devastating
bacterial infectious diseases.
Abstract
After decades of successful treatment of bacterial infections with antibiotics, formerly treatable bacteria have
developed drug resistance and consequently pose a major threat to public health. Since many antibiotics in clinical
development and application still target only a limited set of cellular functions such as cell wall, DNA and protein
synthesis, it is a desirable goal to expand the number and breadth of therapeutic targets combined with a deeper
knowledge about their mechanism. To address this goal, we applied a chemical proteomic strategy termed activitybased protein profiling (ABPP)[1, 2] that is designed to globally profile enzyme activities in complex proteomes. To
identify novel targets for the treatment of multidrug resistant S. aureus (MRSA) strains, we utilized small natural
product derived biomimetic β-lactone[3, 4], β-lactam[5] and cinnamic aldehyde[6] molecules which were modified with
a small tag for the visualization and identification of dedicated targets in complex proteomes by SDS-gelelectrophoresis and mass spectrometry (Figure 1). Structural variations in side chains of selected molecules led to
an increased affinity for certain enzymes that played crucial roles in resistance and virulence.[7, 8] The general utility
of this approach was demonstrated by the chemical inhibition of a central S. aureus virulence regulator that resulted
in a drastically decreased expression of major virulence factors which are key players in e.g. sepsis, tissue necrosis,
inflammation and toxic shock.[9] Since this virulence regulator is highly conserved in many pathogens, our strategy
could represent a global approach for the treatment of infectious diseases by disarming the bacterial virulence
repertoire. Disarmed pathogens could then be easily eliminated by the human immune response. A drug based on
this concept displays many advantages over conventional antibiotics, such as preserving the useful, cooperating
microorganisms e.g. in the digestive tract, and exerting less selective pressure on pathogens, which may result in
decreased resistance development.
Figure 1: Identification of cellular targets of small molecules.
Literature:
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[2]
[3]
[4]
[5]
[6]
[7]
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[9]
M. J. Evans, B. F. Cravatt, Chem Rev 2006, 106, 3279.
S. A. Sieber, B. F. Cravatt, Chem Commun (Camb) 2006, 2311.
T. Böttcher, S. A. Sieber, Angew Chem Int Ed Engl 2008, 47, 4600.
T. Böttcher, S. A. Sieber, J Am Chem Soc 2008, 130, 14400.
I. Staub, S. A. Sieber, J Am Chem Soc 2008, 130, 13400.
M. Pitscheider, S. A. Sieber, Chem Commun (Camb) 2009, 3741.
I. Staub, S. A. Sieber, J Am Chem Soc 2009, 131, 6271.
T. Böttcher, S. A. Sieber, ChemMedChem 2009, 4, 1260.
T. Böttcher, S. A. Sieber, Chembiochem 2009, 10, 663.
All are Welcome