title: Discovery of novel pneumococcal surface antigen A (PsaA) inhibitors using a fragment-based drug design approach.
abstract: Streptococcus pneumoniae is a leading cause of life-threatening bacterial infections, especially in young children in developing countries. Pneumococcal infections can be treated with β-lactam antibiotics, but rapid emergence of multidrug-resistant strains of S. pneumoniae over the past two decades has emphasized the need to identify novel drug targets. Pneumococcal surface antigen A (PsaA) is one such target, found on the cell surface of S. pneumoniae. It functions as a high-affinity substrate-binding protein, facilitating acquisition of Mn(2+), which has an important role in protecting S. pneumoniae from reactive oxygen species and, hence, oxidative stress. Consequently, PsaA is essential for bacterial survival and an important virulence factor, which makes it a promising target for antibiotic drug development. To design novel PsaA inhibitors, we used a combination of de novo fragment-based drug discovery and in silico virtual screening methods. We profiled a collection of low molecular weight compounds that were selected based on their structural diversity and ability to bind to apo-PsaA in a virtual docking experiment. The screening resulted in two initial hits that were further optimized by structural variation to improve their potency while maintaining their ligand efficiency and favorable physicochemical properties. The optimized hits were validated using a cell-based assay and molecular dynamics simulations. We found that virtual screening substantially augmented fragment-based drug design approaches, leading to the identification of novel pneumococcal PsaA inhibitors.
authors: †Institute for Molecular Bioscience, The University of Queensland, St. Lucia, 4072, Australia.
authors: Megha
authors: M
authors: Bajaj
authors: †Institute for Molecular Bioscience, The University of Queensland, St. Lucia, 4072, Australia.
authors: Sreeman K
authors: SK
authors: Mamidyala
authors: †Institute for Molecular Bioscience, The University of Queensland, St. Lucia, 4072, Australia.
authors: Johannes
authors: J
authors: Zuegg
authors: ‡Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide 5005, Australia.
authors: Stephanie L
authors: SL
authors: Begg
authors: ‡Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide 5005, Australia.
authors: Miranda P
authors: MP
authors: Ween
authors: §School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, 4072, Australia.
authors: Zhenyao
authors: Z
authors: Luo
authors: †Institute for Molecular Bioscience, The University of Queensland, St. Lucia, 4072, Australia.
authors: Johnny X
authors: JX
authors: Huang
authors: §School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, 4072, Australia.|∥Australian Infectious Diseases Research Centre, The University of Queensland, St. Lucia, 4072, Australia.
authors: Alastair G
authors: AG
authors: McEwan
authors: †Institute for Molecular Bioscience, The University of Queensland, St. Lucia, 4072, Australia.|§School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, 4072, Australia.|∥Australian Infectious Diseases Research Centre, The University of Queensland, St. Lucia, 4072, Australia.
authors: Bostjan
authors: B
authors: Kobe
authors: ‡Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide 5005, Australia.
authors: James C
authors: JC
authors: Paton
authors: ‡Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide 5005, Australia.
authors: Christopher A
authors: CA
authors: McDevitt
authors: †Institute for Molecular Bioscience, The University of Queensland, St. Lucia, 4072, Australia.
authors: Matthew A
authors: MA
authors: Cooper
mesh_terms: D018829:Adhesins, Bacterial / Q000737:chemistry / Q000235:genetics; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics; D001681:Biological Assay; D002413:Cations, Divalent; D015195:Drug Design; D055808:Drug Discovery; D008024:Ligands; D008074:Lipoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D008345:Manganese / Q000737:chemistry; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000494:pharmacology; D013296:Streptococcus pneumoniae / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
chemical_list: D018829:Adhesins, Bacterial; D000900:Anti-Bacterial Agents; D000942:Antigens, Bacterial; D002413:Cations, Divalent; D008024:Ligands; D008074:Lipoproteins; C085000:PsaA protein, Streptococcus; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D008345:Manganese; D015032:Zinc