Oral Presentation Australian Society for Microbiology Annual Scientific Meeting 2016

Bacterial disarmament: DSB proteins as anti-virulence targets (#15)

Roisin M McMahon 1 , Philip Ireland 2 , Martin J Scanlon 3 , Mitali Sarkar-Tyson 2 4 , Jenny L Martin 1 5
  1. Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia
  2. Defence Science and Technology Laboratory, Porton Down, UK
  3. Department of Medicinal Chemistry, Monash University, Parkville, Melbourne, Victoria, Australia
  4. Marshall Center for Infectious Disease Research and Training, School of Pathology and Laboratory Medicine , University of Western Australia, Perth, WA, Australia
  5. Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia

Antibiotic resistance threatens modern medicine as we know it. We urgently need new antimicrobials and better strategies to preserve their efficacy.

Anti-virulence drugs offer the potential to disarm bacteria, rather than killing them or preventing growth. This promises infection control but in a manner that should confer a reduced selection pressure for resistance development.

DiSulfide Bond (DSB) proteins are a family of foldases that catalyse the oxidative folding of virulence proteins in many bacterial species. DSB proteins engage in protein-protein interactions that we aim to characterise and disrupt using protein crystallography and structure based drug discovery approaches. As part of this endeavour we have assembled a sizeable structural library of diverse bacterial DsbA proteins. I will discuss our rational approaches to the identification of small molecule inhibitors targeting DsbA proteins in Burkholderia pseudomallei, Pseudomonas aeruginosa and Escherichia coli, as well as progress in the structural and biochemical examination of DSB partner protein interactions, as part of a broader aim to characterise this fascinating family of antimicrobial targets.

 

  1. Ireland PMº, McMahon RMº, Marshall L, Halili M, Furlong E, Tay S, Martin JL, Sarkar-Tyson. 2014. Disarming Burkholderia pseudomallei: structural and functional characterization of a disulfide oxidoreductase (DsbA) required for virulence in vivo. Antioxid Redox Signal. 20: 606-617 º co-first author
  2. McMahon RM, Lakshmanane P, Martin JL. 2014. Four Structural Subclasses of the Antivirulence Drug Target Disulfide Oxidoreductase DsbA Provides a Platform for Design of Subclass-Specific Inhibitors. Biochim Biophys Acta 1844:1391-401.
  3. McMahon RM, Coinçon M, Tay S, Heras B, Morton CJ, Scanlon MJ, Martin JL. 2015. Sent packing: protein engineering generates a new crystal form of Pseudomonas aeruginosa DsbA1 with increased catalytic surface accessibility. Acta Cryst. D 71(2386-95)