Seminar: Prof Jenny Martin - JEFFERY LECTURE A tale in two parts: how a search for antivirulence compounds led to the discovery of a shapeshifting copper resistance protein

Tuesday, 13 November 2018 - 12:00pm – Tuesday, 13 November 2018 - 1:00pm  |  CHEMSCI M17

Speaker: Prof Jennifer Martin

Protein disulfide bonds form covalent links between sulfurs of cysteine sidechains and are critical for the folding and function of secreted proteins. There is now overwhelming evidence that these inter-residue bonds play a key role in Gram negative bacterial virulence [1]. This presentation will describe the bacterial machinery that introduce disulfide bonds into folding proteins [2]; explore how these have been used to search for a new class of antibacterial agent [3,4,5]; and outline the serendipitous discovery of a shape-shifting foldase [6] that is not only a target for drug discovery but also provides clues for potential plug-and-play bionanotechnology.

  1. Heras et al (2009) “DSB proteins and bacterial pathogenicity”, Nature Rev Micro, 7:215 - 225.
  2. Shouldice et al (2011) “Structure and function of DsbA, a key oxidative folding catalyst”, Antioxid Redox Signal 14:1729-60
  3. Duprez et al (2015) “Peptide inhibitors of the Escherichia coli DsbA oxidative machinery essential for bacterial virulence”, J Med Chem 58:577-87
  4. Adams*, Sharma* et al (2015) “Application of fragment-based screening to the design of inhibitors of Escherichia coli DsbA”, Angew Chem Int Ed Engl 54:2179-84
  5. Halili*, Bachu*, Lindahl* et al (2015) “Small molecule inhibitors of disulfide bond formation by the bacterial DsbA-DsbB dual enzyme system”, ACS Chemical Biology 10:957-64
  6. Furlong et al (2017) “A shape-shifting redox foldase contributes to Proteus mirabilis copper resistance”, Nature Commun, 8:16065.