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Discovery of Novel Pneumococcal Surface Antigen A (PsaA) Inhibitors Using a Fragment-based Drug Design Approach

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Institute for Molecular Bioscience, The University of Queensland, St. Lucia, 4072, Australia
Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide 5005, 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
Cite this: ACS Chem. Biol. 2015, 10, 6, 1511–1520
Publication Date (Web):March 19, 2015
Copyright © 2015 American Chemical Society

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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 Mn2+, 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.

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This article is cited by 15 publications.

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  3. P.S. Lannes‐Costa, J.S.S. Oliveira, G. Silva Santos, P.E. Nagao. A current review of pathogenicity determinants of Streptococcus sp.. Journal of Applied Microbiology 2021, 131 (4) , 1600-1620.
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  5. F Cools, P Delputte, P Cos. The search for novel treatment strategies for Streptococcus pneumoniae infections. FEMS Microbiology Reviews 2021, 70
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  12. Hyung Jun Kim, Namyoul Kim, David Shum, Srigouri Huddar, Chul Min Park, Soojin Jang. Identification of Antipneumococcal Molecules Effective Against Different Streptococcus pneumoniae Serotypes Using a Resazurin-Based High-Throughput Screen. ASSAY and Drug Development Technologies 2017, 15 (5) , 198-209.
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  15. Chunquan Sheng, Guoqiang Dong, Chen Wang. Computational Fragment-Based Drug Design. 2015, 189-215.

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