Structural Biology of Bacterial Quorum Sensing Signal Transduction

Quorum sensing is a bacterial cell-cell communication process regulated by secreted signaling molecules called autoinducers. At low cell density, in the absence of appreciable amounts of autoinducers, bacteria act as individuals. At high cell density, bacteria respond to the accumulation of autoinducers by synchronizing the gene expression of the community. Thus, quorum sensing allows groups of bacteria to act in unison, synchronizing phenotypic changes such as virulence factor expression, biofilm development, antibiotic production, and bioluminescence.

The overall goal of our research is to determine with atomic detail the molecular mechanisms regulating bacterial signal transduction. We use biochemical, genetic, and biophysical approaches, particularly X-ray crystallography, to study mechanistic aspects of signaling protein function. Ongoing work in our lab is targeting bacterial quorum-sensing receptors and signal relay proteins for crystallization and X-ray structure determination. The X-ray crystal structures of these proteins and protein complexes will answer longstanding and fundamental questions pertaining to bacterial signal transduction. Understanding how extracellular signals regulate quorum sensing, and in turn the induction of virulence in human pathogens, will ultimately enable the rational design of new signaling agonists and antagonists that will serve as lead compounds for antibiotic drug design.

Selected Publications

• Parashar, V., Jeffrey, P.D., and Neiditch, M.B. (2013). Conformational change-induced repeat domain expansion regulates Rap phosphatase quorum-sensing signal receptors. PLoS Biol 11, e1001512.

• Srivastava, D., Hsieh, M.L., Khataokar, A., Neiditch, M.B., and Waters, C.M. (2013). Cyclic di-GMP inhibits Vibrio cholerae motility by repressing induction of transcription and inducing extracellular polysaccharide production. Mol Microbiol.

• Wilson, R., Kumar, P., Parashar, V., Vilcheze, C., Veyron-Churlet, R., Freundlich, J.S.,Barnes, S.W., Walker, J.R., Szymonifka, M.J., Marchiano, E., Shenai, S.,Colangeli, R., Jacobs, W.R., Jr., Neiditch, M.B., Kremer, L., and Alland, D. (2013). Antituberculosis thiophenes define a requirement for Pks13 in mycolic acidbiosynthesis. Nat Chem Biol 9,499-506.

• Parashar, V., Konkol, M.A., Kearns, D.B., and Neiditch, M.B. (2013). A Plasmid-Encoded Phosphatase Regulates Bacillus subtilis Biofilm Architecture, Sporulation, and Genetic Competence. J Bacteriol 195, 2437-2448.

• Baker, M.D., and Neiditch, M.B. (2011). Structural basis of response regulator inhibition by a bacterial anti-activator protein. PLoS Biol 9, e1001226.
  
  
• Sambanthamoorthy, K., Gokhale, A.A., Lao, W., Parashar, V., Neiditch, M.B., Semmelhack, M.F., Lee, I., and Waters, C.M. (2011). Identification of a novel benzimidazole that inhibits bacterial biofilm formation in a broad-spectrum manner. Antimicrob Agents Chemother 55, 4369-4378
  
  
• Mirouze, N., Parashar, V., Baker, M.D., Dubnau, D.A., and Neiditch, M.B. (2011). An Atypical Phr Peptide Regulates the Developmental Switch Protein RapH. J Bacteriol 193, 6197-6206.
  
  
• Rapista, A., Ding, J., Benito, B., Lo, Y.T., Neiditch, M.B., Lu, W., and Chang, T.L. (2011). Human defensins 5 and 6 enhance HIV-1 infectivity through promoting HIV attachment. Retrovirology 8, 45.
  
  
• Parashar, V., Mirouze, N., Dubnau, D.A., and Neiditch, M.B. (2011). Structural basis of response regulator dephosphorylation by rap phosphatases. PLoS Biol 9, e1000589.

• Baker, M.D. and Neiditch, M.B. (2010) "Transmembrane signaling." Bacterial Signaling. Ed. Jung, K. and Kraemer, R. 197-210.
  
  

Training and Positions

2002-07 Postdoctoral Fellow, Princeton University

2002      Ph.D., Baylor College of Medicine