Shaun W. Lee Monahan Family Associate Professor of Rare and Neglected Diseases

Molecular Microbiology and Biosynthesis of Peptide Therapeutics
Shaun W. Lee

Research Interests:

It is our primary research goal to gain a better understanding of the biosynthetic mechanisms underlying bacteriocin production. Our focus is on a particular class of bacteriocins that use a conserved mechanism of posttranslational modification to produce the active toxin. One important member of this family is the highly active cytolysin Streptolysin S (SLS), an important virulence factor produced by the human pathogen Group A Streptococcus pyogenes (GAS). GAS is a leading human pathogen causing common infections such as pharyngitis and impetigo, as well as invasive syndromes such as necrotizing fasciitis and toxic shock syndrome. Gene clusters that resemble the SLS biosynthesis complex are present in several important human pathogens, such as E. coli, Staphylococcus aureus, Listeria monocytogenes, and Clostridium botulinum. Importantly, this class of peptide antibiotics are produced ribosomally, and thus will be amenable to genetic engineering strategies. Furthermore, inhibitors of the posttranslational modifying enzymes will offer new targets for drugs which could be effective against a variety of pathogens. Efforts in our laboratory involve important multidisciplinary avenues – chemical approaches for structural identification of bacteriocins, large-scale screening methods to identify active antibiotic candidates, as well as molecular and microbiology-based approaches to better understand how microorganisms biosynthesize and utilize these bacteriocins.

 

Biography:

  • Assistant Professor, University of Notre Dame, IN
  • Postdoctoral Fellow, University of California, San Diego, CA
  • Ph.D., Oregon Health and Science University, Portland, OR
  • B.A., University of California Berkeley, CA

 

Recent Papers:

  • Fields FR, Carothers KE, Balsara, RD, Ploplis, VA, Castellino, FJ, and Lee, S.W. Rational design of syn-safencin, a novel linear antimicrobial peptide derived from the circular bacteriocins safencin AS-48. 2018. J Antibiotics 71, 592-600.
  • Higashi DL, Biais N, Donahue DL, Mayfield JA, Tessier C, Rodriguez K, Ashfeld B, Luchetti J, Ploplis VA, Castellino FJ, Lee, S.W. Activation of band 3 mediates group A Streptococcus streptolysin S-based beta-haemolysis. Nature Microbiology. 2016. DOI: 10.1038. NMICROBIOL2015.4. *Featured on Cover, Nature Microbiology, Feb 2016.
  • Bao YJ, Liang Z, Mayfield JA, Donahue DL, Carothers KE, Lee, S.W., Ploplis VA, Castellino FJ. Genomic Characterization of a Pattern D Streptococcus pyogenes emm53 Isolate Reveals a Genetic Rationale for Invasive Skin Tropicity. J Bacteriol. 2016 May 27;198(12):1712-24. doi: 10.1128/JB.01019-15.
  • Flaherty RA, Lee, S.W. Implementation of a Permeable Membrane Insert-based Infection System to Study the Effects of Secreted Bacterial Toxins on Mammalian Host Cells. J. Vis. Exp. 2016. (114), e54406, doi:10.3791/54406.
  • Flaherty, R., Freed, S., Lee, S.W. The wide world of Bacteriocins: ribosomally encoded bacterial peptides. 2014. PLOS Pathogens 10(7): e1004221.
  • Thomas, C.L. and Lee, S.W. Knowing is half the battle: Targeting virulence factors of Group A Streptococcus for vaccine and therapeutics. 2012. Curr Drug Targets. 13(3):308-22.
  • Mayfield,J.A. Liang, Z., Agrahari, G., Lee, S.W., Ploplis, V.A., Castellino, F.J. Random Mutations in the Control of Virulence Sensor Gene from Streptococcus pyogenes After Infection in Mice Lead to Clonal Variants With Altered Gene Regulatory Activity and Virulence. 2014. PLOS One. 9(6):e1000698.