Application of Fragment-Based Screening to the Design of Inhibitors of Escherichia coli DsbA†
Dr. Luke A. Adams
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
These authors contributed equally to this work.
Search for more papers by this authorDr. Pooja Sharma
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
These authors contributed equally to this work.
Search for more papers by this authorDr. Biswaranjan Mohanty
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorOlga V. Ilyichova
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Mark D. Mulcair
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Martin L. Williams
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorEllen C. Gleeson
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Makrina Totsika
School of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, QLD 4072 (Australia)
Present address: Institute of Health and Biomedical, Innovation, Queensland University of Technology, Kelvin Grove, QLD 4059 (Australia)
Search for more papers by this authorDr. Bradley C. Doak
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Sofia Caria
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Kieran Rimmer
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. James Horne
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Stephen R. Shouldice
Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072 (Australia)
Search for more papers by this authorMansha Vazirani
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Stephen J. Headey
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorBrent R. Plumb
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorProf. Jennifer L. Martin
Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072 (Australia)
Search for more papers by this authorCorresponding Author
Dr. Begoña Heras
Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072 (Australia)
Present address: La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086 (Australia)
Begoña Heras, Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072 (Australia)
Jamie S. Simpson, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Martin J. Scanlon, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorCorresponding Author
Dr. Jamie S. Simpson
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Begoña Heras, Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072 (Australia)
Jamie S. Simpson, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Martin J. Scanlon, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorCorresponding Author
Dr. Martin J. Scanlon
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Begoña Heras, Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072 (Australia)
Jamie S. Simpson, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Martin J. Scanlon, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Luke A. Adams
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
These authors contributed equally to this work.
Search for more papers by this authorDr. Pooja Sharma
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
These authors contributed equally to this work.
Search for more papers by this authorDr. Biswaranjan Mohanty
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorOlga V. Ilyichova
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Mark D. Mulcair
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Martin L. Williams
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorEllen C. Gleeson
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Makrina Totsika
School of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, QLD 4072 (Australia)
Present address: Institute of Health and Biomedical, Innovation, Queensland University of Technology, Kelvin Grove, QLD 4059 (Australia)
Search for more papers by this authorDr. Bradley C. Doak
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Sofia Caria
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Kieran Rimmer
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. James Horne
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Stephen R. Shouldice
Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072 (Australia)
Search for more papers by this authorMansha Vazirani
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorDr. Stephen J. Headey
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorBrent R. Plumb
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorProf. Jennifer L. Martin
Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072 (Australia)
Search for more papers by this authorCorresponding Author
Dr. Begoña Heras
Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072 (Australia)
Present address: La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086 (Australia)
Begoña Heras, Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072 (Australia)
Jamie S. Simpson, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Martin J. Scanlon, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorCorresponding Author
Dr. Jamie S. Simpson
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Begoña Heras, Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072 (Australia)
Jamie S. Simpson, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Martin J. Scanlon, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorCorresponding Author
Dr. Martin J. Scanlon
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Begoña Heras, Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072 (Australia)
Jamie S. Simpson, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Martin J. Scanlon, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au
Search for more papers by this authorWe acknowledge funding from the National Health and Medical Research Council (grant number 1009785) and the Australian Research Council for an Australian Laureate Fellowship, a Future Fellowship, and a Discovery Early Career Researcher Award to J.L.M., B.H., and M.T., respectively (grant numbers FL0992138, FT130100580, and DE130101169). We thank the Bio21 Institute NMR Facility and the CSIRO Collaborative Crystallisation Centre (www.csiro.au/C3). This research was undertaken on the MX1 and MX2 beamlines at the Australian Synchrotron and at the UQ ROCX Diffraction Facility.
Abstract
The thiol-disulfide oxidoreductase enzyme DsbA catalyzes the formation of disulfide bonds in the periplasm of Gram-negative bacteria. DsbA substrates include proteins involved in bacterial virulence. In the absence of DsbA, many of these proteins do not fold correctly, which renders the bacteria avirulent. Thus DsbA is a critical mediator of virulence and inhibitors may act as antivirulence agents. Biophysical screening has been employed to identify fragments that bind to DsbA from Escherichia coli. Elaboration of one of these fragments produced compounds that inhibit DsbA activity in vitro. In cell-based assays, the compounds inhibit bacterial motility, but have no effect on growth in liquid culture, which is consistent with selective inhibition of DsbA. Crystal structures of inhibitors bound to DsbA indicate that they bind adjacent to the active site. Together, the data suggest that DsbA may be amenable to the development of novel antibacterial compounds that act by inhibiting bacterial virulence.
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References
- 1
- 1aM. A. Cooper, D. Shlaes, Nature 2011, 472, 32;
- 1bB. Obama, Executive Order—Combating antibiotic-resistant bacteria, http://www.whitehouse.gov/the-press-office/2014/09/18/executive-order-combating-antibiotic-resistant-bacteria;
- 1cR. R. Uchil, G. S. Kohli, V. M. Katekhaye, O. C. Swami, J. Clin. Diagn. Res. 2014, 8, ME 01–04;
- 1dWorld Health Organization in Antimicrobial resistance: global report on surveillance 2014;
- 1eG. D. Wright, Chem. Biol. 2012, 19, 3– 10.
- 2J. Fernebro, Drug Resist. Updates 2011, 14, 125–139.
- 3
- 3aR. C. Allen, R. Popat, S. P. Diggle, S. P. Brown, Nat. Rev. Microbiol. 2014, 12, 300–308;
- 3bB. Heras, M. J. Scanlon, J. L. Martin, Br. J. Clin. Pharmacol. 2014, DOI: ;
- 3cD. A. Rasko, V. Sperandio, Nat. Rev. Drug Discovery 2010, 9, 117–128.
- 4
- 4aA. K. Barczak, D. T. Hung, Curr. Opin. Microbiol. 2009, 12, 490–496;
- 4bA. E. Clatworthy, E. Pierson, D. T. Hung, Nat. Chem. Biol. 2007, 3, 541–548;
- 4cS. A. Stanley, D. T. Hung, Biochemistry 2009, 48, 8776–8786;
- 4dM. Zucca, S. Scutera, D. Savoia, Mini-Rev. Med. Chem. 2011, 11, 888–900.
- 5B. Heras, S. R. Shouldice, M. Totsika, M. J. Scanlon, M. A. Schembri, J. L. Martin, Nat. Rev. Microbiol. 2009, 7, 215–225.
- 6J. L. Martin, J. C. Bardwell, J. Kuriyan, Nature 1993, 365, 464–468.
- 7K. Inaba, S. Murakami, M. Suzuki, A. Nakagawa, E. Yamashita, K. Okada, K. Ito, Cell 2006, 127, 789–801.
- 8V. Früh, Y. Zhou, D. Chen, C. Loch, E. Ab, Y. N. Grinkova, H. Verheij, S. G. Sligar, J. H. Bushweller, G. Siegal, Chem. Biol. 2010, 17, 881–891.
- 9T. Miki, N. Okada, H. Danbara, J. Biol. Chem. 2004, 279, 34631–34642.
- 10P. M. Ireland, R. M. McMahon, L. E. Marshall, M. Halili, E. Furlong, S. Tay, J. L. Martin, M. Sarkar-Tyson, Antioxid. Redox Signaling 2014, 20, 606–617.
- 11M. Totsika, B. Heras, D. J. Wurpel, M. A. Schembri, J. Bacteriol. 2009, 191, 3901–3908.
- 12J. J. Paxman, N. A. Borg, J. Horne, P. E. Thompson, Y. Chin, P. Sharma, J. S. Simpson, J. Wielens, S. Piek, C. M. Kahler, H. Sakellaris, M. Pearce, S. P. Bottomley, J. Rossjohn, M. J. Scanlon, J. Biol. Chem. 2009, 284, 17835–17845.
- 13T. L. Nero, C. J. Morton, J. K. Holien, J. Wielens, M. W. Parker, Nat. Rev. Cancer 2014, 14, 248–262.
- 14M. Mayer, B. Meyer, Angew. Chem. Int. Ed. 1999, 38, 1784–1788;
10.1002/(SICI)1521-3773(19990614)38:12<1784::AID-ANIE1784>3.0.CO;2-Q CAS PubMed Web of Science® Google ScholarAngew. Chem. 1999, 111, 1902–1906.10.1002/(SICI)1521-3757(19990614)111:12<1902::AID-ANGE1902>3.0.CO;2-O Web of Science® Google Scholar
- 15F. Kurth, K. Rimmer, L. Premkumar, B. Mohanty, W. Duprez, M. A. Halili, S. R. Shouldice, B. Heras, D. P. Fairlie, M. J. Scanlon, J. L. Martin, PLoS One 2013, 8, e 80210.
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