title: Structure-based design, synthesis, and study of potent inhibitors of beta-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents.
abstract: Fatty acid biosynthesis is essential for bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-ACP synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Small molecules that inhibit FabH enzymatic activity have the potential to be candidates within a novel class of selective, nontoxic, broad-spectrum antibacterials. Using crystallographic structural information on these highly conserved active sites and structure based drug design principles, a benzoylaminobenzoic acid series of compounds was developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity against Gram-positive and selected Gram-negative organisms.
authors.affiliation: Departments of Medicinal Chemistry, Protein Biochemistry and Structural Biology, Quorex Pharmaceuticals Inc., 1890 Rutherford Road, Suite 200, Carlsbad, CA 92008, USA. zhenie@phoenixpharmaco.com
authors.forename: Zhe
authors.initials: Z
authors.lastname: Nie
authors.forename: Carin
authors.initials: C
authors.lastname: Perretta
authors.forename: Jia
authors.initials: J
authors.lastname: Lu
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.forename: Stephen
authors.initials: S
authors.lastname: Margosiak
authors.forename: Ketan S
authors.initials: KS
authors.lastname: Gajiwala
authors.forename: Joseph
authors.initials: J
authors.lastname: Cortez
authors.forename: Victor
authors.initials: V
authors.lastname: Nikulin
authors.forename: Kraig M
authors.initials: KM
authors.lastname: Yager
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Appelt
authors.forename: Shaosong
authors.initials: S
authors.lastname: Chu
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D003460:Crystallization; D015195:Drug Design; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C077402:3-ketoacyl-acyl carrier protein synthase III; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase