title: Potent, novel in vitro inhibitors of the Pseudomonas aeruginosa deacetylase LpxC.
abstract: Deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by LpxC is the first committed step in the Pseudomonas aeruginosa biosynthetic pathway to lipid A; homologous enzymes are found widely among Gram-negative bacteria. As an essential enzyme for which no inhibitors have yet been reported, the P. aeruginosa LpxC represents a highly attractive target for a novel antibacterial drug. We synthesized several focused small-molecule libraries, each composed of a variable aromatic ring, one of four heterocyclic/spacer moieties, and a hydroxamic acid and evaluated the LpxC inhibition of these compounds against purified P. aeruginosa enzyme. To ensure that the in vitro assay would be as physiologically relevant as possible, we synthesized a tritiated form of the specific P. aeruginosa glycolipid substrate and measured directly the enzymatically released acetate. Several of our novel compounds, predominantly those having fluorinated substituents on the aromatic ring and an oxazoline as the heterocyclic moiety, demonstrated in vitro IC(50) values less than 1 microM. We now report the synthesis and in vitro evaluation of these P. aeruginosa LpxC inhibitors.
authors.affiliation: Chiron Corporation, 201 Elliot Avenue West, Seattle, WA 98119, USA. t.kline@seagen.com
authors.forename: Toni
authors.initials: T
authors.lastname: Kline
authors.forename: Niels H
authors.initials: NH
authors.lastname: Andersen
authors.forename: Eric A
authors.initials: EA
authors.lastname: Harwood
authors.forename: Jason
authors.initials: J
authors.lastname: Bowman
authors.forename: Andre
authors.initials: A
authors.lastname: Malanda
authors.forename: Stephanie
authors.initials: S
authors.lastname: Endsley
authors.forename: Alice L
authors.initials: AL
authors.lastname: Erwin
authors.forename: Michael
authors.initials: M
authors.lastname: Doyle
authors.forename: Susan
authors.initials: S
authors.lastname: Fong
authors.forename: Alex L
authors.initials: AL
authors.lastname: Harris
authors.forename: Brian
authors.initials: B
authors.lastname: Mendelsohn
authors.forename: Khisimuzi
authors.initials: K
authors.lastname: Mdluli
authors.forename: Christian R H
authors.initials: CR
authors.lastname: Raetz
authors.forename: C Kendall
authors.initials: CK
authors.lastname: Stover
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Witte
authors.forename: Asha
authors.initials: A
authors.lastname: Yabannavar
authors.forename: Shuguang
authors.initials: S
authors.lastname: Zhu
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D010078:Oxazines; D010080:Oxazoles; D013844:Thiazoles; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase