4CV1: Crystal Structure Of S. Aureus Fabi In Complex With Nadph And Cg400549

Determining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549, a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-acyl carrier protein reductase (FabI), has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus infections, which constitute a serious threat to human health. In this study, we solved the structures of three different FabI homologues in complex with several pyridone inhibitors, including CG400549. Based on these structures, we rationalize the 65-fold reduced affinity of CG400549 toward Escherichia coli versus S. aureus FabI and implement concepts to improve the spectrum of antibacterial activity. The identification of different conformational states along the reaction coordinate of the enzymatic hydride transfer provides an elegant visual depiction of the relationship between catalysis and inhibition, which facilitates rational inhibitor design. Ultimately, we developed the novel 4-pyridone-based FabI inhibitor PT166 that retained favorable pharmacokinetics and efficacy in a mouse model of S. aureus infection with extended activity against Gram-negative and mycobacterial organisms.
PDB ID: 4CV1Download
MMDB ID: 119172
PDB Deposition Date: 2014/3/22
Updated in MMDB: 2014/08
Experimental Method:
x-ray diffraction
Resolution: 1.95  Å
Source Organism:
Similar Structures:
Biological Unit for 4CV1: tetrameric; determined by author and by software (PISA)
Molecular Components in 4CV1
Label Count Molecule
Proteins (4 molecules)
Enoyl-[acyl-carrier-protein] Reductase [nadh]
Molecule annotation
Chemicals (15 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB