LESLIE BW, ALLANSON NM, BARKER JJ, COYNE MJ, GILL AE, GOURLEY DG, LEWENDON A, PRIMROSE WU, THOMAS MG, THOMSON SP, TYLER PD; Interscience Conference on Antimicrobial Agents and Chemotherapy (42nd : 2002 : San Diego, Calif.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2002 Sep 27-30; 42: abstract no. F-759.
PanTherix Ltd, Glasgow, United Kingdom
BACKGROUND: Phosphopantetheine adenylyltransferase (PPAT), an enzyme in the Coenzyme A biosynthetic pathway, is essential for bacterial viability and inhibitors of PPAT are potential antibacterial agents. Methods and RESULTS: Crystal structures of the apo-forms of the enzymes of E. coli and S. aureus were determined. In parallel, an extensive library of chemically diverse small molecules was screened against E. coli PPAT using a proprietary assay, identifying, amongst other inhibitors, the anthranilate (1) (E. coli PPAT IC[50] = 1.8 microM, S. aureus PPAT IC[50] = 50 microM). The structure of the complex of (1) with E. coli PPAT was determined, and the resultant structural information was used to design more potent inhibitors, exemplified by (2) (E. coli PPAT IC[50] = 3.3 microM, S. aureus PPAT = 5.3 microM). Differences in potency between the two species could be explained by detailed analysis of high-resolution X-ray crystal structures. Subtle but significant differences between the E. coli and S. aureus enzymes revealed the importance of shape-complementarity. Compound (1) had an MIC against S. aureus of 0.5 microg/mL and reduced the levels of intracellular Coenzyme A in intact bacteria. [figure: see text] Conclusion: Using structure-based design, a series of antibacterial anthranilates, which act on a novel target enzyme, and which have low micromolar MICs against several pathogenic Gram-positive bacteria, was identified.
Publication Types:
Keywords:
- Anthranilic Acids
- Anti-Bacterial Agents
- Coenzyme A
- Crystallization
- Microbial Sensitivity Tests
- Nucleotidyltransferases
- anthranilic acid
- pantetheine-phosphate adenylyltransferase
Other ID:
UI: 102267896
From Meeting Abstracts