Poster Presentation The 43rd Lorne Conference on Protein Structure and Function 2018

Optimisation of EcDsbA inhibitors by fragment based drug design (#247)

Rebecca Whitehouse 1 , Tony Wang 2 , Olga Ilyichova 1 , Begoña Heras 2 , Jennifer L Martin 3 , Bradley Doak 1 , Peter Scammells 1 , Martin Scanlon 1
  1. Monash Institute of pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
  2. La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia
  3. Griffith Institute of Drug Discovery, Griffith University, Nathan, Queensland, Australia

Multi-drug resistant strains of bacteria are on the rise creating a need for the development of novel antimicrobials1. Targeting bacterial virulence rather than viability has been proposed to slow the development of resistance and the diversity of virulence factors in different bacteria provides many novel anti-virulence targets2. DsbA is a bacterial enzyme that catalyses the formation of disulfide bonds in the periplasm of many Gram-negative bacteria3. DsbA is a key regulator of virulence, which is required for the correct folding of many virulence factors making it an attractive drug target. Fragment-Based Drug Design (FBDD) was utilised to identify starting points in our efforts to generate inhibitors of DsbA. FBDD has been demonstrated to be an effective approach to identify starting points for the design of inhibitors for difficult to drug targets4. Past fragment screens against EcDsbA have identified many weakly binding starting points for optimisation into functional inhibitors of DsbA.

In the current presentation I will describe our work to improve affinity and selectivity by the addition of reactive functional groups to covalently modify the active site of DsbA. Additionally, the assessment of their inhibitory activity and the evaluation of their utility as chemical probes to study kinetics and enzymatic activity of EcDsbA.

  1. World Health Organization. Antimicrobial resistance: Global report on surveillance. 2014
  2. Rasko DA, Sperandio V. Anti-virulence strategies to combat bacteria-mediated disease. Nat Rev Drug Discov. 2010;9(2):117-28
  3. Heras, B, Shouldice, SR, Totsika M, Scanlon, MJ, Schembri MA, Martin JL. DSB proteins and bacterial pathogenicity. Nat Rev Micro. 2009;7(3):215-25
  4. Erlanson DA, Fesik SW, Hubbard RE, Jahnke W, Jhoti H. Twenty years on: The impact of fragments on drug discovery. Nat Rev Drug Discov. 2016:15(9):605-19.