Oral Presentation 2014 International Biophysics Congress

Bacterial disarmament: DSB proteins as anti-virulence targets (#55)

Roisin M. McMahon 1 , Philip Ireland 2 , Kieran Rimmer 3 , Lakshmanane Premkumar 1 , Mitali Sarkar-Tyson 2 , Craig Morton 4 , Martin J. Scanlon 3 5 , Jennifer L. Martin 1
  1. Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
  2. Defence Science and Technology Laboratory, Porton Down, UK
  3. Department of Medicinal Chemistry, Monash University, Melbourne, VIC, Australia
  4. Biota Holdings Limited, Melbourne, VIC, Australia
  5. ARC Centre for Coherent Xray Science, Monash University, Melbourne, VIC , Australia

A rapid rise in antibiotic resistance coupled with a decline in new antibiotics is generating a public health crisis. For the next generation of therapeutics, it is anticipated that a strategy of anti-virulence – drugs that disarm, but do not kill bacteria - will yield antimicrobials that control infection but exert a reduced selection pressure to acquire drug resistance, offering the tantilising prospect of antibiotics without resistance.

DiSulfide Bond (DSB) proteins are essential for the assembly of numerous bacterial virulence factors making them one such target.1 Deletion of DiSulfide Bond protein A (DsbA) prevents lethal bacterial infection in vivo 2 and has pleiotropic effects on virulence.1 DSB proteins engage in a number of protein-protein interactions that we aim to disrupt by combining fragment based drug discovery programs with crystallographic structural characterisation of a library of bacterial DSB proteins.

We have recently determined the high-resolution crystal structure of Burkholderia pseudomallei DsbA2, and conducted a fragment library screen against Pseudomonas aeruginosa DsbA (PaDsbA) that identified small molecules that bind selectively to PaDsbA on the opposite face from the active site surface. For the tightest binding fragment, NMR solution and X-ray crystal structures provide high-resolution molecular information about protein-fragment interactions, and a starting point for hit-to-lead elaboration.

Comparative structural analyses of 13 DsbA proteins to explore the druggability of this family of enzymes identified four structural DsbA classes differentiated by topology and active site surface features3; these subclasses suggest an exciting potential for the development of DsbA inhibitors with subclass-wide spectrum of activity.