4J1N: Crystal Structures Of Fabi From F. Tularensis In Complex With Novel Inhibitors Based On The Benzimidazole Scaffold

Citation:
Abstract
Francisella tularensis, the causative agent of tularemia, presents a significant biological threat and is a Category A priority pathogen due to its potential for weaponization. The bacterial FASII pathway is a viable target for the development of novel antibacterial agents treating Gram-negative infections. Here we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided lead optimization strategy, and the determination of several co-crystal structures that confirm the binding mode of designed inhibitors. These compounds display an improved low nanomolar enzymatic activity as well as promising low microgram/mL antibacterial activity against both F. tularensis and Staphylococcus aureus and its methicillin-resistant strain (MRSA). The improvements in activity accompanying structural modifications lead to a better understanding of the relationship between the chemical structure and biological activity that encompasses both enzymatic and whole-cell activity.
PDB ID: 4J1NDownload
MMDB ID: 121669
PDB Deposition Date: 2013/2/1
Updated in MMDB: 2014/11
Experimental Method:
x-ray diffraction
Resolution: 2.45  Å
Source Organism:
Similar Structures:
Biological Unit for 4J1N: dimeric; determined by author and by software (PISA)
Molecular Components in 4J1N
Label Count Molecule
Proteins (2 molecules)
2
Enoyl-[acyl-carrier-protein] Reductase [nadh]
Molecule annotation
Chemicals (5 molecules)
1
2
2
2
3
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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