Biochemistry and Molecular Biology
Penn State Science
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Timothy  C. Meredith

Timothy C. Meredith

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  • Assistant Professor of Biochemistry and Molecular Biology
206 South Frear Laboratory
University Park, PA 16802
Email: txm50@psu.edu
Phone: (814) 867-5909

Research Interests

Our research focuses on the bacterial cell envelope, and in particular on lipid metabolism, across a set of key human pathogens including Staphylococcus aureus and Pseudomonas aeruginosa.

The bacterial envelope is composed of a typical phospholipid bilayer common to all cells that is encased within a unique peptidoglycan polymer mesh consisting of glycan strands crosslinked by oligopeptides.  In Gram negative bacteria, there is an additional asymmetric outermembrane lipid bilayer containing the saccharolipid lipopolysaccharide.  Beyond being a requisite structural element that imparts structural rigidity, the cell envelope regulates the uptake of nutrients, the exclusion of toxins, and is at the forefront of host-pathogen interactions.  We use a combination of biochemistry, bacterial genetics, and functional genomics to understand how the cell envelope is assembled, maintained, and altered by cellular programs in response to complex environmental stimuli.  By uncovering and characterizing cell envelope related genetic determinants responsible for cell envelope biogenesis, we aim to establish strategies for new antibiotic development, characterize antibiotic resistance mechanisms, and uncover factors that enhance virulence.

Graduate Programs

BMMB

Research Summary


Functional genomics in Staphylococcus aureus

Methicillin resistant Staphylococcus aureus (MRSA) is a leading cause of hospital acquired infections, and ever increasingly outside of the clinic with the rise of hyper virulent community acquired S. aureus lineages.  With nearly 30% of the ~3 Mb genome subject to genetic exchange (via plasmids, transposons, bacteriophage, etc.), S. aureus demonstrates remarkable genomic plasticity that confers a high level of adaptability.  Certain members within clonal complexes account for a disproportionate number of infections.  We are interested in understanding the molecular determinants that impart increased fitness, focusing on contemporary clinical isolates. 

We have developed a comprehensive phage based delivery transposon system in S. aureus to generate high coverage libraries in diverse strains belonging to widely circulating clonal complexes.  Each cassette contains a distinct promoter or transcriptional terminator element of varying intrinsic strength, so a gradient of gene expression levels can be achieved proximal to the insertion site.

Meredith Figure 1

Meredith Figure 2

By installing a unique 4-bp DNA barcode on each cassette, the different cassettes can be pulled in a single transposon library, probed for phenotype, and then de-multiplexed using the DNA bar code tag in a massively parallel fashion using next generation sequencing.  In collaboration with Suzanne Walker’s laboratory (Department of Microbiology and Immunobiology, Harvard Medical School), we have identified a number of uncharacterized cell envelop related genes involved in resistance to clinically relevant cell envelope targeting antibiotics, and are currently determining their function. 

Lipid metabolism in Pseudomonas aeruginosa

Meredith Figure 4Fatty acid synthesis occupies a central role in Pseudomonas aeruginosa cell envelope physiology and infection biology.  In addition to supplying acyl chains for membrane phospholipids and the outermembrane saccharolipid lipopolysaccharide, FAS is required for acylation of quorum sensing signals, siderophore assembly, and lipoproteins. Our group recently discovered a new class of fatty acid biosynthesis initiation enzymes (PA5174, renamed FabY) which is only present in the aeruginosa sp. sub group of Pseudomonads 1.  When overexpressed ectopically, virulence factor production and quorum sensing signaling was significantly enhanced.  In addition, we also discovered a new medium chain fatty acid metabolic shunt pathway involving the previously unannotated gene PA3286, that directly funnels exogenous fatty acids back into de novo biosynthesis.  We are interested in understanding how these unique
P. aeruginosa FAS elements are integrated into cell envelop biogenesis, environmental sensing, and lipid metabolism.

Selected Publications

  1. Escherichia coli YrbH is a D-arabinose 5-phosphate isomerase
    Meredith, T.C. and Woodard, R.W. J. Biol. Chem. 2003 278(35): 32771-7
  2. Identification of GutQ from Escherichia coli as a D-arabinose 5-phosphate isomerase
    Meredith, T.C. and Woodard, R.W. J. Bacteriol. 2005 187(20): 6936-42
  3. Redefining the requisite lipopolysaccharide structure in Escherichia coli
    Meredith, T.C., Aggarwal, P., Mamat, U., Lindner, B. and Woodard, R.W. ACS Chem. Biol. 2006 1(1): 33-42
  4. Modification of lipopolysaccharide with colanic acid (M-antigen) repeats in Escherichia coli
    Meredith, T.C., Mamat, U., Kaczynski, Z, Lindner, B, Holst, O, and Woodard, R.W. J. Biol. Chem. 2007 282(11): 7790-8
  5. Single amino acid substitutions in either YhjD or MsbA confer viability to 3-deoxy-D-manno-oct-2-ulosonic acid-depleted Escherichia coli
    Mamat, U., Meredith, T.C., Aggarwal, P., Kühl, A., Kirchhoff, P., Lindner, B., Hanuszkiewicz, A., Sun, J., Holst, O., and Woodard R.W. Mol. Microbiol. 2008 67(3): 633-48
  6. Late-stage polyribitol phosphate wall teichoic acid biosynthesis in Staphylococcus aureus
    Meredith, T.C., Swoboda, J.G., and Walker, S. J. Bacteriol. 2008 190(8): 3046-56
  7. WaaA of the Hyperthermophilic Bacterium Aquifex aeolicus is a Monofunctional 3-deoxy-d-manno-oct-2-ulosonic Acid Transferase Involved in Lipopolysaccharide Biosynthesis
    Mamat, U., Schmidt,  H., Munoz, E., Lindner ,B., Fukase, K., Hanuszkiewicz, A., Meredith, T.C., Woodard, R.W., Hilgenfeld, R., Mesters, J.R., and Holst, O. J. Biol. Chem. 2009 284(33): 22248-62
  8. Discovery of a Small Molecule that Blocks Wall Teichoic Acid Biosynthesis in Staphylococcus aureus
    Swoboda, J.G.*, Meredith T.C.*, Campbell, J., Brown, S., Suzuki, T., Bollenbach, T., Malhowski,  A.J., Kishony, R., Gilmore, M.S., and Walker, S. ACS Chem Biol. 2009 4(10):875-83
  9. Wall teichoic acid function, biosynthesis, and inhibition
    Swoboda, J.G., Campbell, J., Meredith, T.C., and Walker, S. Chembiochem. 2010 11(1): 35-45
  10. Staphylococcus aureus and Bacillus subtilis W23 make polyribitol wall teichoic acids using different enzymatic pathways
    Brown, S., Meredith, T.C., Swoboda, J.G., and Walker, S. Chem. Biol. 2010 17(10):1101-10
  11. A unique arabinose 5-phosphate isomerase found within a genomic island associated with the uropathogenicity of Escherichia coli CFT073
    Mosberg, J.A., Yep, A., Meredith,T.C., Smith, S., Wang, P.F.,  Holler,T., Mobley, H., Woodard, R. J. Bacteriol. 2011 193(12): 2981-8
  12. High-frequency transposition for determining antibacterial mode of action
    Wang, H., Claveau, D., Vaillancourt, J., Roemer, T., and Meredith, T.C. Nature Chem. Biol. 2011 7(10): 720-9
  13. Antagonism of Chemical Genetic Interaction Networks Re-sensitize MRSA to β-lactam Antibiotics
    Lee, S.H., Jarantow, L.W., Wang, H., Sillaots, S., Cheng, H., Meredith, T.C., Thompson, J., and Roemer, T.  Chem. & Biol. 2011 18(11): 1379-1389
  14. Fatty acid biosynthesis in Pseudomonas aeruginosa is initiated by FabY: A new class of β-ketoacyl acyl carrier protein synthases
    Yuan, Y., Sachdeeva, M., Leeds, J.A., and Meredith, T.C. J. Bacteriol. 2012 194(19): 5171-84
  15. Pseudomonas aeruginosa directly shunts β-oxidation degradation intermediates into de novo fatty acid biosynthesis Yuan, Y., Leeds, J.A., and Meredith, T.C.  J. Bacteriol. 2012 194(19): 5185-96
  16. Harnessing the Power of Transposon Mutagenesis for Antibacterial Target Identification   Meredith, T.C.*, Wang, H., Beaulieu, P., Gründling, A., and Roemer, T.* Mob. Gen. Elem. 2012 2(4): 171-17
  17. Methicillin Resistance in S. aureus Depends on β-O-GlcNAcylation of Wall Teichoic Acids Brown, S., Xia, G., Luhachack, L.G., Campbell, J., Meredith, T.C., Chen, C., Winstel, V., Gekeler, C., Irazoqui, J.E., Peschel, A., and Walker, S. PNAS 2012 109(46): 18909-14
  18. Discovery of Wall Teichoic Acid Inhibitors as Potential Anti-MRSA β-Lactam Combination Agents
    Wang, H., Gill, C.J., Lee, S.H., Mann, P., Zuck, P., Meredith, T.C., Murgolo, N., She, S., Kales, S., Liang, L., Liu, J., Wu, J., Santa Maria, J., Su, J., Pan, J., Hailey, J., Mcguinness, D., Tan, C.T., Flattery, A., Walker, S., Black, T., and Roemer, T. Chem. & Biol. 2013 20(2): 272–284
  19. Pleiotropic regulatory genes bldA, adpA and absB are implicated in production of phosphoglycolipid antibiotic moenomycin
    Makitrynskyy, R., Ostash, B., Tsypik, O., Rebets, Y., Doud, E., Meredith, T.C., Luzhetskyy, A., Bechthold, A., Walker, S., and Fedorenko V. Open Biol. 2013 3(10): 130121
  20. On the essentiality of lipopolysaccharide to Gram-negative bacteria
    Zhang, G., Meredith, T.C., and Kahne, D. Curr Opin Microbiol. 2013 16(6):779-85
  21. Deletion of the β-Acetoacetyl Synthase FabY in Pseudomonas aeruginosa induces hypoacylation of lipopolysaccharide and increases antimicrobial susceptibility Six, D.A., Yuan, Y., Leeds, J.A., and Meredith, T.C.  Antimicrob. Agents Chemother. 2014 58(1):153-61