Structures of Staphylococcus aureus peptide deformylase in complex with two classes of new inhibitors

Lee, S. J., Lee, S. K., Yoon, H. J., Lee, H. H., Kim, K. K., Lee, B. J., Il Lee, B., Suh, S. W. (July 2012) Structures of Staphylococcus aureus peptide deformylase in complex with two classes of new inhibitors. Acta Crystallographica Section D-Biological Crystallography, 68 (Part 7). pp. 784-793. ISSN 0907-4449

[img]
Preview
PDF (Paper)
Lee Acta Crystallogr D 2012.pdf - Published Version

Download (1568Kb) | Preview
URL: http://www.ncbi.nlm.nih.gov/pubmed/22751663
DOI: 10.1107/s0907444912011912

Abstract

Peptide deformylase (PDF) catalyzes the removal of the formyl group from the N-terminal methionine residue in newly synthesized polypeptides, which is an essential process in bacteria. Four new inhibitors of PDF that belong to two different classes, hydroxamate/pseudopeptide compounds [PMT387 (7a) and PMT497] and reverse-hydroxamate/nonpeptide compounds [PMT1039 (15e) and PMT1067], have been developed. These compounds inhibited the growth of several pathogens involved in respiratory-tract infections, such as Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae, and leading nosocomial pathogens such as Staphylococcus aureus and Klebsiella pneumoniae with a minimum inhibitory concentration (MIC) in the range 0.1-0.8 mg ml(-1). Interestingly, the reverse-hydroxamate/nonpeptide compounds showed a 250-fold higher antimicrobial activity towards S. aureus, although the four compounds showed similar K-i values against S. aureus PDF enzymes, with Ki values in the 11-85 nM range. To provide a structural basis for the discovery of additional PDF inhibitors, the crystal structures of S. aureus PDF in complex with the four inhibitors were determined at resolutions of 1.90-2.30 angstrom. The inhibitor-bound structures displayed distinct deviations depending on the inhibitor class. The distance between the Zn2+ ion and the carbonyl O atom of the hydroxamate inhibitors (or the hydroxyl O atom of the reverse-hydroxamate inhibitors) appears to be correlated to S. aureus inhibition activity. The structural information reported in this study should aid in the discovery of new PDF inhibitors that can be used as novel antibacterial drugs.

Item Type: Paper
Uncontrolled Keywords: occurring antibacterial agent crystal-structures escherichia-coli polypeptide deformylase hydroxamic acid drug design actinonin lbm415 target crystallography
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
organism description > bacteria
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Joshua-Tor lab
Depositing User: Matt Covey
Date: July 2012
Date Deposited: 30 Jan 2013 17:23
Last Modified: 30 Jan 2013 17:23
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26989

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving