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Peptide inhibitors of the Escherichia coli DsbA oxidative machinery essential for bacterial virulence

Journal Article


Abstract


  • One approach to address antibiotic resistance is to develop drugs that interfere with bacterial virulence. A master regulator of virulence in Gram-negative bacteria is the oxidative folding machinery comprising DsbA and DsbB. A crystal structure at 2.5 Å resolution is reported here for Escherichia coli DsbA complexed with PFATCDS, a heptapeptide derived from the partner protein Escherichia coli DsbB. Details of the peptide binding mode and binding site provide valuable clues for inhibitor design. Structure-activity relationships for 30 analogues were used to produce short peptides with a cysteine that bind tightly to EcDsbA (Kd = 2.0 ± 0.3 μM) and inhibit its activity (IC50 = 5.1 ± 1.1 μM). The most potent inhibitor does not bind to or inhibit human thioredoxin that shares a similar active site. This finding suggests that small molecule inhibitors can be designed to exploit a key interaction of EcDsbA, as the basis for antivirulence agents with a novel mechanism of action.

UOW Authors


  •   Duprez, Wilko (external author)
  •   Premkumar, Lakshmanane (external author)
  •   Halili, Maria (external author)
  •   Lindahl, Fredrik (external author)
  •   Reid, Robert (external author)
  •   Fairlie, David P. (external author)
  •   Martin, Jennifer

Publication Date


  • 2015

Citation


  • Duprez, W., Premkumar, L., Halili, M. A., Lindahl, F., Reid, R. C., Fairlie, D. P. & Martin, J. L. (2015). Peptide inhibitors of the Escherichia coli DsbA oxidative machinery essential for bacterial virulence. Journal of Medicinal Chemistry, 58 (2), 577-587.

Scopus Eid


  • 2-s2.0-84921470541

Number Of Pages


  • 10

Start Page


  • 577

End Page


  • 587

Volume


  • 58

Issue


  • 2

Place Of Publication


  • United States

Abstract


  • One approach to address antibiotic resistance is to develop drugs that interfere with bacterial virulence. A master regulator of virulence in Gram-negative bacteria is the oxidative folding machinery comprising DsbA and DsbB. A crystal structure at 2.5 Å resolution is reported here for Escherichia coli DsbA complexed with PFATCDS, a heptapeptide derived from the partner protein Escherichia coli DsbB. Details of the peptide binding mode and binding site provide valuable clues for inhibitor design. Structure-activity relationships for 30 analogues were used to produce short peptides with a cysteine that bind tightly to EcDsbA (Kd = 2.0 ± 0.3 μM) and inhibit its activity (IC50 = 5.1 ± 1.1 μM). The most potent inhibitor does not bind to or inhibit human thioredoxin that shares a similar active site. This finding suggests that small molecule inhibitors can be designed to exploit a key interaction of EcDsbA, as the basis for antivirulence agents with a novel mechanism of action.

UOW Authors


  •   Duprez, Wilko (external author)
  •   Premkumar, Lakshmanane (external author)
  •   Halili, Maria (external author)
  •   Lindahl, Fredrik (external author)
  •   Reid, Robert (external author)
  •   Fairlie, David P. (external author)
  •   Martin, Jennifer

Publication Date


  • 2015

Citation


  • Duprez, W., Premkumar, L., Halili, M. A., Lindahl, F., Reid, R. C., Fairlie, D. P. & Martin, J. L. (2015). Peptide inhibitors of the Escherichia coli DsbA oxidative machinery essential for bacterial virulence. Journal of Medicinal Chemistry, 58 (2), 577-587.

Scopus Eid


  • 2-s2.0-84921470541

Number Of Pages


  • 10

Start Page


  • 577

End Page


  • 587

Volume


  • 58

Issue


  • 2

Place Of Publication


  • United States