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



Research
Selected Publications
Biography
Honors & Awards
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.




Ruiz N, Silhavy TJ. How Escherichia coli Became the Flagship Bacterium of Molecular Biology. J Bacteriol. 2022 ;204(9):e0023022. PubMed
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Sun J, Rutherford ST, Silhavy TJ, Huang KCasey. Physical properties of the bacterial outer membrane. Nat Rev Microbiol. 2022 ;20(4):236-248. PubMed
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Combs AN, Silhavy TJ. The sacrificial adaptor protein Skp functions to remove stalled substrates from the β-barrel assembly machine. Proc Natl Acad Sci U S A. 2022 ;119(1). PubMed
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Benn G, Mikheyeva IV, Inns PGeorge, Forster JC, Ojkic N, Bortolini C, et al. Phase separation in the outer membrane of . Proc Natl Acad Sci U S A. 2021 ;118(44). PubMed
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Guest RL, Rutherford ST, Silhavy TJ. Border Control: Regulating LPS Biogenesis. Trends Microbiol. 2021 ;29(4):334-345. PubMed
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Silhavy TJ. Acknowledgment of Reviewers. J Bacteriol. 2020 ;202(24). PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. mSystems. 2020 ;5(4). PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. Microbiol Resour Announc. 2020 ;9(32). PubMed
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Silhavy TJ. Time To Go. J Bacteriol. 2020 ;203(1). PubMed
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Silhavy TJ. 2020 Jack Kenney Award for Outstanding Service. J Bacteriol. 2020 ;203(1). PubMed
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Grimm J, Shi H, Wang W, Mitchell AM, Wingreen NS, Huang KCasey, et al. 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. PubMed
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Hart EM, Silhavy TJ. Functions of the BamBCDE Lipoproteins Revealed by Bypass Mutations in BamA. J Bacteriol. 2020 ;202(21). PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. J Virol. 2020 ;94(20). PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. J Clin Microbiol. 2020 ;58(10). PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. Antimicrob Agents Chemother. 2020 ;64(10). PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. Infect Immun. 2020 ;88(10). PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. Clin Microbiol Rev. 2020 ;33(4). PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. Mol Cell Biol. 2020 ;40(19). PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. J Bacteriol. 2020 ;202(19). PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. Appl Environ Microbiol. 2020 ;86(18). PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. Microbiol Mol Biol Rev. 2020 ;84(3). PubMed
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Hart EM, Gupta M, Wühr M, Silhavy TJ. 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. PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. mSphere. 2020 ;5(4). PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. mBio. 2020 ;11(4). PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. Microbiol Spectr. 2020 ;8(3). PubMed
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Guest RL, Guerra DSamé, Wissler M, Grimm J, Silhavy TJ. YejM Modulates Activity of the YciM/FtsH Protease Complex To Prevent Lethal Accumulation of Lipopolysaccharide. mBio. 2020 ;11(2). PubMed
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Schloss PD, Junior M, Alvania R, Arias CA, Baumler A, Casadevall A, et al. The ASM Journals Committee Values the Contributions of Black Microbiologists. J Microbiol Biol Educ. 2020 ;21(2). PubMed
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Silhavy TJ. Current Issues in Scientific Publishing. J Bacteriol. 2019 ;. PubMed
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Silhavy TJ. Olaf Schneewind, 1961-2019: Scientist, Mentor, Friend. J Bacteriol. 2019 ;. PubMed
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Silhavy TJ. Acknowledgment of Reviewers. J Bacteriol. 2019 ;201(24). PubMed
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Silhavy TJ. 2019 Jack Kenney Award for Outstanding Service. J Bacteriol. 2019 ;202(1). PubMed
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Hart EM, Mitchell AM, Konovalova A, Grabowicz M, Sheng J, Han X, et al. 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. PubMed
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Mitchell AM, Silhavy TJ. Envelope stress responses: balancing damage repair and toxicity. Nat Rev Microbiol. 2019 ;17(7):417-428. PubMed
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Hart EM, O'Connell A, Tang K, Wzorek JS, Grabowicz M, Kahne D, et al. Fine-Tuning of σ Activation Suppresses Multiple Assembly-Defective Mutations in Escherichia coli. J Bacteriol. 2019 ;201(11). PubMed
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Silhavy TJ, Mitchell AM. Genetic Analysis of Protein Translocation. Protein J. 2019 ;38(3):217-228. PubMed
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Hart EM, Gupta M, Wühr M, Silhavy TJ. The Synthetic Phenotype of Δ Δ Double Mutants Results from a Lethal Jamming of the Bam Complex by the Lipoprotein RcsF. mBio. 2019 ;10(3). PubMed
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Ricci DP, Silhavy TJ. Outer Membrane Protein Insertion by the β-barrel Assembly Machine. EcoSal Plus. 2019 ;8(2). PubMed
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Silhavy TJ. 2018 Jack Kenney Award for Outstanding Service. J Bacteriol. 2019 ;201(1). PubMed
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Silhavy TJ. State of the Journal. J Bacteriol. 2019 ;201(1). PubMed
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Mitchell AM, Srikumar T, Silhavy TJ. Cyclic Enterobacterial Common Antigen Maintains the Outer Membrane Permeability Barrier of Escherichia coli in a Manner Controlled by YhdP. mBio. 2018 ;9(4). PubMed
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Konovalova A, Grabowicz M, Balibar CJ, Malinverni JC, Painter RE, Riley D, et al. 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. PubMed
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May KL, Silhavy TJ. Erratum for May and Silhavy, "The Escherichia coli Phospholipase PldA Regulates Outer Membrane Homeostasis via Lipid Signaling". mBio. 2018 ;9(3). PubMed
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May KL, Silhavy TJ. The Phospholipase PldA Regulates Outer Membrane Homeostasis via Lipid Signaling. mBio. 2018 ;9(2). PubMed
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Lee J, Sutterlin HA, Wzorek JS, Mandler MD, Hagan CL, Grabowicz M, et al. 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. PubMed
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Silhavy TJ. 2017 Jack Kenney Award for Outstanding Service. J Bacteriol. 2018 ;200(1). PubMed
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Silhavy TJ. State of the Journal. J Bacteriol. 2018 ;200(1). PubMed
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May KL, Silhavy TJ. Making a membrane on the other side of the wall. Biochim Biophys Acta Mol Cell Biol Lipids. 2017 ;1862(11):1386-1393. PubMed
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Silhavy TJ. Acknowledgment of Ad Hoc Reviewers. J Bacteriol. 2017 ;199(24). PubMed
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Soltes GR, Martin NR, Park E, Sutterlin HA, Silhavy TJ. Distinctive Roles for Periplasmic Proteases in the Maintenance of Essential Outer Membrane Protein Assembly. J Bacteriol. 2017 ;199(20). PubMed
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McCabe AL, Ricci D, Adetunji M, Silhavy TJ. Conformational Changes That Coordinate the Activity of BamA and BamD Allowing β-Barrel Assembly. J Bacteriol. 2017 ;199(20). PubMed
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Rowland EA, Greco TM, Snowden CK, McCabe AL, Silhavy TJ, Cristea IM. Sirtuin Lipoamidase Activity Is Conserved in Bacteria as a Regulator of Metabolic Enzyme Complexes. mBio. 2017 ;8(5). PubMed
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Konovalova A, Kahne DE, Silhavy TJ. Outer Membrane Biogenesis. Annu Rev Microbiol. 2017 ;71:539-556. PubMed
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Armitage JP, Becker A, Christie PJ, de Boer PAJ, DiRita VJ, Gourse RL, et al. Classic Spotlights: Selected Highlights from the First 100 Years of the . J Bacteriol. 2017 ;199(13). PubMed
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Grabowicz M, Silhavy TJ. Redefining the essential trafficking pathway for outer membrane lipoproteins. Proc Natl Acad Sci U S A. 2017 ;114(18):4769-4774. PubMed
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Grabowicz M, Silhavy TJ. Envelope Stress Responses: An Interconnected Safety Net. Trends Biochem Sci. 2017 ;42(3):232-242. PubMed
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Mitchell AM, Wang W, Silhavy TJ. Novel RpoS-Dependent Mechanisms Strengthen the Envelope Permeability Barrier during Stationary Phase. J Bacteriol. 2017 ;199(2). PubMed
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Silhavy TJ. 2016 Jack Kenney Award for Outstanding Service. J Bacteriol. 2017 ;199(1). PubMed
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Silhavy TJ. State of the Journal. J Bacteriol. 2017 ;199(1). PubMed
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Sutterlin HA, Shi H, May KL, Miguel A, Khare S, Huang KCasey, et al. 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. PubMed
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Silhavy TJ. Classic Spotlight: the Birth of the Transcriptional Activator. J Bacteriol. 2016 ;198(5):744. PubMed
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Casadevall A, Bertuzzi S, Buchmeier MJ, Davis RJ, Drake H, Fang FC, et al. ASM Journals Eliminate Impact Factor Information from Journal Websites. mSystems. 2016 ;1(4). PubMed
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Casadevall A, Bertuzzi S, Buchmeier MJ, Davis RJ, Drake H, Fang FC, et al. ASM Journals Eliminate Impact Factor Information from Journal Websites. mSphere. 2016 ;1(4). PubMed
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Soltes GR, Schwalm J, Ricci DP, Silhavy TJ. The Activity of Escherichia coli Chaperone SurA Is Regulated by Conformational Changes Involving a Parvulin Domain. J Bacteriol. 2016 ;198(6):921-9. PubMed
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Grabowicz M, Koren D, Silhavy TJ. The CpxQ sRNA Negatively Regulates Skp To Prevent Mistargeting of β-Barrel Outer Membrane Proteins into the Cytoplasmic Membrane. mBio. 2016 ;7(2):e00312-16. PubMed
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Casadevall A, Bertuzzi S, Buchmeier MJ, Davis RJ, Drake H, Fang FC, et al. ASM Journals Eliminate Impact Factor Information from Journal Websites. Clin Microbiol Rev. 2016 ;29(4):i-ii. PubMed
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Casadevall A, Bertuzzi S, Buchmeier MJ, Davis RJ, Drake H, Fang FC, et al. ASM Journals Eliminate Impact Factor Information from Journal Websites. Appl Environ Microbiol. 2016 ;82(18):5479-80. PubMed
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Konovalova A, Schwalm JA, Silhavy TJ. A Suppressor Mutation That Creates a Faster and More Robust σE Envelope Stress Response. J Bacteriol. 2016 ;198(17):2345-51. PubMed
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Casadevall A, Bertuzzi S, Buchmeier MJ, Davis RJ, Drake H, Fang FC, et al. ASM Journals Eliminate Impact Factor Information from Journal Websites. Antimicrob Agents Chemother. 2016 ;60(9):5109-10. PubMed
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Casadevall A, Bertuzzi S, Buchmeier MJ, Davis RJ, Drake H, Fang FC, et al. ASM Journals Eliminate Impact Factor Information from Journal Websites. Microbiol Mol Biol Rev. 2016 ;80(3):i-ii. PubMed
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Casadevall A, Bertuzzi S, Buchmeier MJ, Davis RJ, Drake H, Fang FC, et al. ASM Journals Eliminate Impact Factor Information from Journal Websites. J Clin Microbiol. 2016 ;54(9):2216-7. PubMed
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Lee J, Xue M, Wzorek JS, Wu T, Grabowicz M, Gronenberg LS, et al. Characterization of a stalled complex on the β-barrel assembly machine. Proc Natl Acad Sci U S A. 2016 ;113(31):8717-22. PubMed
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Mahoney TF, Ricci DP, Silhavy TJ. Classifying β-Barrel Assembly Substrates by Manipulating Essential Bam Complex Members. J Bacteriol. 2016 ;198(14):1984-92. PubMed
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Casadevall A, Bertuzzi S, Buchmeier MJ, Davis RJ, Drake H, Fang FC, et al. ASM Journals Eliminate Impact Factor Information from Journal Websites. mBio. 2016 ;7(4). PubMed
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Konovalova A, Mitchell AM, Silhavy TJ. A lipoprotein/β-barrel complex monitors lipopolysaccharide integrity transducing information across the outer membrane. Elife. 2016 ;5. PubMed
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Okuda S, Sherman DJ, Silhavy TJ, Ruiz N, Kahne D. Lipopolysaccharide transport and assembly at the outer membrane: the PEZ model. Nat Rev Microbiol. 2016 ;14(6):337-45. PubMed
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Silhavy TJ. Classic Spotlight: a Very Pleiotropic Mutant. J Bacteriol. 2016 ;198(3):371. PubMed
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Silhavy TJ. Classic Spotlight: Gram-Negative Bacteria Have Two Membranes. J Bacteriol. 2016 ;198(2):201. PubMed
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Silhavy TJ. 2015 Jack Kenney Award for Outstanding Service. J Bacteriol. 2016 ;198(1):4. PubMed
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Silhavy TJ. The Journal of Bacteriology Is 100. J Bacteriol. 2016 ;198(1):1-3. PubMed
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Konovalova A, Silhavy TJ. Outer membrane lipoprotein biogenesis: Lol is not the end. Philos Trans R Soc Lond B Biol Sci. 2015 ;370(1679). PubMed
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Grabowicz M, Yeh J, Silhavy TJ. Dominant negative lptE mutation that supports a role for LptE as a plug in the LptD barrel. J Bacteriol. 2013 ;195(6):1327-34. PubMed
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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