Thomas J. Silhavy

Contact
tsilhavy@princeton.eduFaculty Assistant
Jennifer MunkoEducation
- B.S., Pharmacy, Ferris State College
- A.M., Ph.D., Biochemistry, Harvard University
Research Area
Microbiology & VirologyResearch Focus
Protein targeting and signal transductionMembrane 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.
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The ASM Journals Committee Values the Contributions of Black Microbiologists. J Clin Microbiol. 2020 ;58(10). .
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The ASM Journals Committee Values the Contributions of Black Microbiologists. Infect Immun. 2020 ;88(10). .
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The ASM Journals Committee Values the Contributions of Black Microbiologists. J Bacteriol. 2020 ;202(19). .
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Functions of the BamBCDE Lipoproteins Revealed by Bypass Mutations in BamA. J Bacteriol. 2020 ;202(21). .
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Border Control: Regulating LPS Biogenesis. Trends Microbiol. 2020 ;. .
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Acknowledgment of Reviewers. J Bacteriol. 2020 ;202(24). .
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The ASM Journals Committee Values the Contributions of Black Microbiologists. mSystems. 2020 ;5(4). .
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The ASM Journals Committee Values the Contributions of Black Microbiologists. Microbiol Resour Announc. 2020 ;9(32). .
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Time To Go. J Bacteriol. 2020 ;203(1). .
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2020 Jack Kenney Award for Outstanding Service. J Bacteriol. 2020 ;203(1). .
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The inner membrane protein YhdP modulates the rate of anterograde phospholipid flow in . Proc Natl Acad Sci U S A. 2020 ;117(43):26907-26914. .
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The ASM Journals Committee Values the Contributions of Black Microbiologists. J Virol. 2020 ;94(20). .
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The ASM Journals Committee Values the Contributions of Black Microbiologists. Antimicrob Agents Chemother. 2020 ;64(10). .
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The ASM Journals Committee Values the Contributions of Black Microbiologists. Clin Microbiol Rev. 2020 ;33(4). .
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The ASM Journals Committee Values the Contributions of Black Microbiologists. Mol Cell Biol. 2020 ;40(19). .
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The ASM Journals Committee Values the Contributions of Black Microbiologists. Appl Environ Microbiol. 2020 ;86(18). .
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The ASM Journals Committee Values the Contributions of Black Microbiologists. Microbiol Mol Biol Rev. 2020 ;84(3). .
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The gain-of-function allele bypasses the essential requirement for BamD in β-barrel outer membrane protein assembly. Proc Natl Acad Sci U S A. 2020 ;117(31):18737-18743. .
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The ASM Journals Committee Values the Contributions of Black Microbiologists. mSphere. 2020 ;5(4). .
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The ASM Journals Committee Values the Contributions of Black Microbiologists. mBio. 2020 ;11(4). .
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The ASM Journals Committee Values the Contributions of Black Microbiologists. Microbiol Spectr. 2020 ;8(3). .
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The ASM Journals Committee Values the Contributions of Black Microbiologists. J Microbiol Biol Educ. 2020 ;21(2). .
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Current Issues in Scientific Publishing. J Bacteriol. 2019 ;. .
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Olaf Schneewind, 1961-2019: Scientist, Mentor, Friend. J Bacteriol. 2019 ;. .
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Acknowledgment of Reviewers. J Bacteriol. 2019 ;201(24). .
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2019 Jack Kenney Award for Outstanding Service. J Bacteriol. 2019 ;202(1). .
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A small-molecule inhibitor of BamA impervious to efflux and the outer membrane permeability barrier. Proc Natl Acad Sci U S A. 2019 ;116(43):21748-21757. .
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Envelope stress responses: balancing damage repair and toxicity. Nat Rev Microbiol. 2019 ;17(7):417-428. .
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Fine-Tuning of σ Activation Suppresses Multiple Assembly-Defective Mutations in Escherichia coli. J Bacteriol. 2019 ;201(11). .
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Genetic Analysis of Protein Translocation. Protein J. 2019 ;38(3):217-228. .
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Outer Membrane Protein Insertion by the β-barrel Assembly Machine. EcoSal Plus. 2019 ;8(2). .
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State of the Journal. J Bacteriol. 2019 ;201(1). .
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2018 Jack Kenney Award for Outstanding Service. J Bacteriol. 2019 ;201(1). .
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Inhibitor of intramembrane protease RseP blocks the σ response causing lethal accumulation of unfolded outer membrane proteins. Proc Natl Acad Sci U S A. 2018 ;115(28):E6614-E6621. .
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The Phospholipase PldA Regulates Outer Membrane Homeostasis via Lipid Signaling. mBio. 2018 ;9(2). .
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Substrate binding to BamD triggers a conformational change in BamA to control membrane insertion. Proc Natl Acad Sci U S A. 2018 ;115(10):2359-2364. .
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2017 Jack Kenney Award for Outstanding Service. J Bacteriol. 2018 ;200(1). .
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State of the Journal. J Bacteriol. 2018 ;200(1). .
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Making a membrane on the other side of the wall. Biochim Biophys Acta Mol Cell Biol Lipids. 2017 ;1862(11):1386-1393. .
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Acknowledgment of Ad Hoc Reviewers. J Bacteriol. 2017 ;199(24). .
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Distinctive Roles for Periplasmic Proteases in the Maintenance of Essential Outer Membrane Protein Assembly. J Bacteriol. 2017 ;199(20). .
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Conformational Changes That Coordinate the Activity of BamA and BamD Allowing β-Barrel Assembly. J Bacteriol. 2017 ;199(20). .
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Outer Membrane Biogenesis. Annu Rev Microbiol. 2017 ;71:539-556. .
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Classic Spotlights: Selected Highlights from the First 100 Years of the . J Bacteriol. 2017 ;199(13). .
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Redefining the essential trafficking pathway for outer membrane lipoproteins. Proc Natl Acad Sci U S A. 2017 ;114(18):4769-4774. .
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Envelope Stress Responses: An Interconnected Safety Net. Trends Biochem Sci. 2017 ;42(3):232-242. .
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Novel RpoS-Dependent Mechanisms Strengthen the Envelope Permeability Barrier during Stationary Phase. J Bacteriol. 2017 ;199(2). .
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State of the Journal. J Bacteriol. 2017 ;199(1). .
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2016 Jack Kenney Award for Outstanding Service. J Bacteriol. 2017 ;199(1). .
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Disruption of lipid homeostasis in the Gram-negative cell envelope activates a novel cell death pathway. Proc Natl Acad Sci U S A. 2016 ;113(11):E1565-74. .
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Classic Spotlight: the Birth of the Transcriptional Activator. J Bacteriol. 2016 ;198(5):744. .
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ASM Journals Eliminate Impact Factor Information from Journal Websites. mSystems. 2016 ;1(4). .
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ASM Journals Eliminate Impact Factor Information from Journal Websites. mSphere. 2016 ;1(4). .
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The Activity of Escherichia coli Chaperone SurA Is Regulated by Conformational Changes Involving a Parvulin Domain. J Bacteriol. 2016 ;198(6):921-9. .
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ASM Journals Eliminate Impact Factor Information from Journal Websites. Clin Microbiol Rev. 2016 ;29(4):i-ii. .
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ASM Journals Eliminate Impact Factor Information from Journal Websites. Appl Environ Microbiol. 2016 ;82(18):5479-80. .
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A Suppressor Mutation That Creates a Faster and More Robust σE Envelope Stress Response. J Bacteriol. 2016 ;198(17):2345-51. .
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ASM Journals Eliminate Impact Factor Information from Journal Websites. Antimicrob Agents Chemother. 2016 ;60(9):5109-10. .
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ASM Journals Eliminate Impact Factor Information from Journal Websites. Microbiol Mol Biol Rev. 2016 ;80(3):i-ii. .
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ASM Journals Eliminate Impact Factor Information from Journal Websites. J Clin Microbiol. 2016 ;54(9):2216-7. .
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Characterization of a stalled complex on the β-barrel assembly machine. Proc Natl Acad Sci U S A. 2016 ;113(31):8717-22. .
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Classifying β-Barrel Assembly Substrates by Manipulating Essential Bam Complex Members. J Bacteriol. 2016 ;198(14):1984-92. .
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ASM Journals Eliminate Impact Factor Information from Journal Websites. mBio. 2016 ;7(4). .
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Lipopolysaccharide transport and assembly at the outer membrane: the PEZ model. Nat Rev Microbiol. 2016 ;14(6):337-45. .
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Classic Spotlight: a Very Pleiotropic Mutant. J Bacteriol. 2016 ;198(3):371. .
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Classic Spotlight: Gram-Negative Bacteria Have Two Membranes. J Bacteriol. 2016 ;198(2):201. .
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2015 Jack Kenney Award for Outstanding Service. J Bacteriol. 2016 ;198(1):4. .
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The Journal of Bacteriology Is 100. J Bacteriol. 2016 ;198(1):1-3. .
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Outer membrane lipoprotein biogenesis: Lol is not the end. Philos Trans R Soc Lond B Biol Sci. 2015 ;370(1679). .
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Dominant negative lptE mutation that supports a role for LptE as a plug in the LptD barrel. J Bacteriol. 2013 ;195(6):1327-34. .
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