Thomas J. Silhavy

Thomas J. Silhavy
Warner-Lambert Parke-Davis Professor of Molecular Biology

Contact

tsilhavy@princeton.edu
609-258-5899
Thomas Laboratory, 310
Silhavy Lab

Faculty Assistant

Jennifer Munko

Education

  • B.S., Pharmacy, Ferris State College
  • A.M., Ph.D., Biochemistry, Harvard University

Research Area

Microbiology & Virology

Research Focus

Protein targeting and signal transduction

Membrane biogenesis and signal transduction

All cells have subcellular compartments that are bound by lipid bilayers, and this three-dimensional organization is essential for life. If we consider lipid bilayers themselves as compartments, then Gram-negative bacteria, such as Escherichia coli, have four distinct subcellular locations: the cytoplasm, inner membrane (IM), periplasm, and outer membrane (OM). The noncytoplasmic compartments are collectively termed the cell envelope. We wish to understand cellular assembly, in particular, the process of OM biogenesis. The OM is an asymmetric lipid bilayer containing phospholipids in the inner leaflet and lipopolysaccharide (LPS) in the outer leaflet. Membrane spanning outer membrane proteins (OMPs) typically assume a beta-barrel conformation. All OM components are synthesized in the cytoplasm or the IM and therefore, OM biogenesis requires the transport of these molecules across the cell envelope for assembly at their final cellular location. Strikingly, these assembly processes occur outside the peptidoglycan cell wall in an environment that lacks an obvious energy source such as ATP. We use a combination of genetics, biochemistry, and bioinformatics to identify and characterize the cellular machinery required for these assembly reactions. We also study the signal transduction systems that monitor the integrity of the cell envelope and regulate the production of effector proteins that combat stress.

The OM is an effective permeability barrier and because of this organelle Gram-negative bacteria are almost always more resistant to antibiotics than are Gram-positive bacteria. The essential OM assembly components we have identified represent attractive new drug targets. Indeed, these targets are accessible at the cell surface and thus not protected either by the OM barrier or by efflux pumps. But what is particularly intriguing is that even if they did not ki inhibitors would disrupt the OM barrier rendering strains more sensitive to existing antibiotics and thus could be especially effective in combination therapies. The more we learn about the OM barrier and how it is made, the more rational and sophisticated our approaches to find small molecule inhibitors.

Thomas J. Silhavy is the Warner-Lambert Parke-Davis Professor of Molecular Biology at Princeton University. Silhavy is a bacterial geneticist who has made fundamental contributions to several different research fields. He is best known for his work on protein secretion, membrane biogenesis, and signal transduction. Using Escherichia coli as a model system, his lab was the first to isolate signal sequence mutations, to identify a component of cellular protein secretion machinery, and an integral membrane component of the outer membrane assembly machinery, and to identify and characterize a two-component regulatory system. Current work in his lab is focused on the mechanisms of outer membrane biogenesis and the regulatory systems that sense and respond to envelope stress and trigger the developmental pathway that allows cells to survive starvation. He is the author of more than 275 research articles and three books.

Professor Silhavy received his BS in Pharmacy (summa cum laude, 1971) from Ferris State College and his MS (1974) and PhD (1975) in Biological Chemistry from Harvard University. As a graduate student with Winfried Boos he helped characterize the role of periplasmic binding proteins in sugar transport. As a postdoctoral fellow with Jonathan Beckwith at Harvard Medical School he helped establish gene fusions as an experimental tool. He served as an Instructor of Microbiology at Harvard Medical School for two years, and he worked at the NCI Frederick Cancer Research Facility for five years where he was Director of the Laboratory of Genetics and Recombinant DNA. He came to Princeton in 1984 as a founding member of the Department of Molecular Biology.

In recognition of his scientific accomplishments, Silhavy was awarded an honorary Doctor of Sciences degree from his alma mater, Ferris State College (1982), was elected Fellow of the American Academy of Microbiology (1994), the American Association for the Advancement of Science (2004), and the American Academy of Arts and Sciences (2005), and he is a member of the National Academy of Sciences (2005) and an associate member of EMBO (2008). In 1999 he received an NIH MERIT award, and he received the Novitski Prize for creativity from the Genetics Society of America in 2008, and the American Society for Microbiology (ASM) Lifetime Achievement Award in 2016. His commitment to teaching is evidenced by the President’s Award for Distinguished Teaching at Princeton (1993), the Graduate Microbiology Teaching award from the American Society for Microbiology (2002), and the Graduate Advising Award at Princeton (2003).

2012

  • Appointed Editor-in-Chief of the Journal of Bacteriology, American Society for Microbiology
  • Appointed Editor-in-Chief of the Journal of Bacteriology, American Society for Microbiology