Virtual Screening of Peptide and Peptidomimetic Fragments Targeted to Inhibit Bacterial Dithiol Oxidase DsbA

Duprez, Wilko, Bachu, Prabhakar, Stoermer, Martin J, Tay, Stephanie, McMahon, Roisin M, Fairlie, David P and Martin, Jennifer L (2015) Virtual Screening of Peptide and Peptidomimetic Fragments Targeted to Inhibit Bacterial Dithiol Oxidase DsbA. Plos One, 10 7: . doi:10.1371/journal.pone.0133805

Author Duprez, Wilko
Bachu, Prabhakar
Stoermer, Martin J
Tay, Stephanie
McMahon, Roisin M
Fairlie, David P
Martin, Jennifer L
Title Virtual Screening of Peptide and Peptidomimetic Fragments Targeted to Inhibit Bacterial Dithiol Oxidase DsbA
Journal name Plos One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2015-07-30
Year available 2015
Sub-type Article (original research)
DOI 10.1371/journal.pone.0133805
Open Access Status DOI
Volume 10
Issue 7
Total pages 16
Place of publication San Francisco, United States
Publisher Public Library of Science
Collection year 2016
Language eng
Formatted abstract
Antibacterial drugs with novel scaffolds and new mechanisms of action are desperately needed to address the growing problem of antibiotic resistance. The periplasmic oxidative folding system in Gram-negative bacteria represents a possible target for anti-virulence antibacterials. By targeting virulence rather than viability, development of resistance and side effects (through killing host native microbiota) might be minimized. Here, we undertook the design of peptidomimetic inhibitors targeting the interaction between the two key enzymes of oxidative folding, DsbA and DsbB, with the ultimate goal of preventing virulence factor assembly. Structures of DsbB - or peptides - complexed with DsbA revealed key interactions with the DsbA active site cysteine, and with a hydrophobic groove adjacent to the active site. The present work aimed to discover peptidomimetics that target the hydrophobic groove to generate non-covalent DsbA inhibitors. The previously reported structure of a Proteus mirabilis DsbA active site cysteine mutant, in a non-covalent complex with the heptapeptide PWATCDS, was used as an in silico template for virtual screening of a peptidomimetic fragment library. The highest scoring fragment compound and nine derivatives were synthesized and evaluated for DsbA binding and inhibition. These experiments discovered peptidomimetic fragments with inhibitory activity at millimolar concentrations. Although only weakly potent relative to larger covalent peptide inhibitors that interact through the active site cysteine, these fragments offer new opportunities as templates to build non-covalent inhibitors. The results suggest that non-covalent peptidomimetics may need to interact with sites beyond the hydrophobic groove in order to produce potent DsbA inhibitors.
Keyword Disulfide Bond Formation
Antimicrobial Agents
Conformer Generation
Clinical Pipeline
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 2 times in Thomson Reuters Web of Science Article | Citations
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