Oral Presentation RACI Biomolecular Division Conference 2013

Targeting DsbA, a key Player in Bacterial Virulence, through the Evolution of a Phenylthiazole Fragment Hit (#41)

Luke A Adams 1 , Biswaranjan Mohanty 1 2 , Olga Ilyichova 1 , Mansha Vazirani 1 , Martin Williams 1 2 , Bradley Doak 1 , Mark Mulcair 1 , Kieran Rimmer 1 , Ellen Gleeson 1 , Brent Plumb 1 , Jennifer L Martin 3 , Begoña Heras 4 , Jamie S Simpson 1 , Martin J Scanlon 1 2
  1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Melbourne, Victoria 3052, Australia
  2. ARC Centre of Excellence for Coherent X-ray Science, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Melbourne, Victoria 3052, Australia
  3. Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia
  4. Department of Biochemistry, La Trobe University, Melbourne, Victoria 3086, Australia

There is an urgent need to develop new antibiotics due to the increasing occurrence of bacterial resistance to the current set of antibacterial agents, as highlighted by a recent report by the World Health Organization.1 

Bacteria utilise a number of virulence factors to cause infection. These virulence factors are typically proteins and many require disulfide bonds to impart structure and stability when excreted into the extracellular environment. In Gram-negative bacteria the enzyme DsbA catalyses the formation of disulfide bonds within these virulence factors. Bacteria that do not possess an active DsbA have been shown to be avirulent and the loss of virulence can in many cases be linked to lack of disulfide bond formation in a DsbA substrate.2 Therefore inhibition of DsbA may lead to a new class of antibacterials that target virulence. It is likely that antivirulence agents would be under less selection pressure for the development of resistance since they would not directly inhibit bacterial growth or viability.

Screening a fragment library against DsbA from Escherichia coli (EcDsbA) using Saturation Transfer Difference (STD)-NMR spectroscopy led to identification of a number of small-molecule hits that were subsequently verified by 1H-15N HSQC experiments. The work presented will focus on a phenylthiazole class of targets identified from the initial fragment screen, outlining our approach to fragment elaboration through synthesis, structure activity relationships and X-ray structural data.

  1. World Health Organization. The evolving threat of antimicrobial resistance - options for action. 2012.
  2. Heras, B.; Shouldice, S. R.; Totsika, M.; Scanlon, M. J.; Schembri, M. A.; Martin, J. L. DSB proteins and bacterial pathogenicity. Nature Rev. Microbiol. 2009, 7, 215-225.