title: Fragment library screening identifies hits that bind to the non-catalytic surface of Pseudomonas aeruginosa DsbA1.
abstract: At a time when the antibiotic drug discovery pipeline has stalled, antibiotic resistance is accelerating with catastrophic implications for our ability to treat bacterial infections. Globally we face the prospect of a future when common infections can once again kill. Anti-virulence approaches that target the capacity of the bacterium to cause disease rather than the growth or survival of the bacterium itself offer a tantalizing prospect of novel antimicrobials. They may also reduce the propensity to induce resistance by removing the strong selection pressure imparted by bactericidal or bacteriostatic agents. In the human pathogen Pseudomonas aeruginosa, disulfide bond protein A (PaDsbA1) plays a central role in the oxidative folding of virulence factors and is therefore an attractive target for the development of new anti-virulence antimicrobials. Using a fragment-based approach we have identified small molecules that bind to PaDsbA1. The fragment hits show selective binding to PaDsbA1 over the DsbA protein from Escherichia coli, suggesting that developing species-specific narrow-spectrum inhibitors of DsbA enzymes may be feasible. Structures of a co-complex of PaDsbA1 with the highest affinity fragment identified in the screen reveal that the fragment binds on the non-catalytic surface of the protein at a domain interface. This biophysical and structural data represent a starting point in the development of higher affinity compounds, which will be assessed for their potential as selective PaDsbA1 inhibitors.
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Biswaranjan
authors.initials: B
authors.lastname: Mohanty
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Kieran
authors.initials: K
authors.lastname: Rimmer
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, Division of Chemistry and Structural Biology, Brisbane, Queensland, Australia.
authors.forename: Róisín M
authors.initials: RM
authors.lastname: McMahon
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Headey
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Mansha
authors.initials: M
authors.lastname: Vazirani
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, Division of Chemistry and Structural Biology, Brisbane, Queensland, Australia.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Shouldice
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, Division of Chemistry and Structural Biology, Brisbane, Queensland, Australia.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Coinçon
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, Division of Chemistry and Structural Biology, Brisbane, Queensland, Australia.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tay
authors.affiliation: Biota Holdings Limited, Notting Hill, Victoria, Australia.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Morton
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Jamie S
authors.initials: JS
authors.lastname: Simpson
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, Division of Chemistry and Structural Biology, Brisbane, Queensland, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martin
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Martin J
authors.identifier: http://orcid.org/0000-0002-9230-7506
authors.initials: MJ
authors.lastname: Scanlon
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D054852:Small Molecule Libraries; D037521:Virulence Factors; D019704:Protein Disulfide-Isomerases