Four structural subclasses of the antivirulence drug target disulfide oxidoreductase DsbA provide a platform for design of subclass-specific inhibitors.
By catalyzing oxidative protein folding, the bacterial disulfide bond protein A (DsbA) plays an essential role in the assembly of many virulence factors. Predictably, DsbA disruption affects multiple downstream effector molecules, resulting in pleiotropic effects on the virulence of important human pathogens. These findings mark DsbA as a master regulator of virulence, and identify the enzyme as a target for a new class of antivirulence agents that disarm pathogenic bacteria rather than killing them. The purpose of this article is to discuss and expand upon recent findings on DsbA and to provide additional novel insights into the druggability of this important disulfide oxidoreductase by comparing the structures and properties of 13 well-characterized DsbA enzymes. Our structural analysis involved comparison of the overall fold, the surface properties, the conformations of three loops contributing to the binding surface and the sequence identity of residues contributing to these loops. Two distinct structural classes were identified, classes I and II, which are differentiated by their central β-sheet arrangements and which roughly separate the DsbAs produced by Gram-negative from Gram-positive organisms. The classes can be further subdivided into a total of four subclasses on the basis of surface features. Class Ia is equivalent to the Enterobacteriaceae class that has been defined previously. Bioinformatic analyses support the classification of DsbAs into 3 of the 4 subclasses, but did not pick up the 4th subclass which is only apparent from analysis of DsbA electrostatic surface properties. In the context of inhibitor development, the discrete structural subclasses provide a platform for developing DsbA inhibitory scaffolds with a subclass-wide spectrum of activity. We expect that more DsbA classes are likely to be identified, as enzymes from other pathogens are explored, and we highlight the issues associated with structure-based inhibitor development targeting this pivotal mediator of bacterial virulence. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia. Electronic address: r.mcmahon@imb.uq.edu.au.
Róisín M
RM
McMahon
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia. Electronic address: p.lakshmanane@uq.edu.au.
Lakshmanane
L
Premkumar
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia. Electronic address: j.martin@imb.uq.edu.au.
Jennifer L
JL
Martin
D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D019704:Protein Disulfide-Isomerases / Q000737:chemistry* / Q000145:classification*; D014774:Virulence / Q000187:drug effects*; D037521:Virulence Factors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D037521:Virulence Factors; D019704:Protein Disulfide-Isomerases
Antibiotic resistance; Antivirulence; Disulfide bond formation; DsbA; Structural classification