Potent, novel in vitro inhibitors of the Pseudomonas aeruginosa deacetylase LpxC.
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.
Kline
Toni
T
Chiron Corporation, 201 Elliot Avenue West, Seattle, WA 98119, USA. t.kline@seagen.com
Andersen
Niels H
NH
Harwood
Eric A
EA
Bowman
Jason
J
Malanda
Andre
A
Endsley
Stephanie
S
Erwin
Alice L
AL
Doyle
Michael
M
Fong
Susan
S
Harris
Alex L
AL
Mendelsohn
Brian
B
Mdluli
Khisimuzi
K
Raetz
Christian R H
CR
Stover
C Kendall
CK
Witte
Pamela R
PR
Yabannavar
Asha
A
Zhu
Shuguang
S
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
D004791:Enzyme Inhibitors; D010078:Oxazines; D010080:Oxazoles; D013844:Thiazoles; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase