title: Antibacterial agents that inhibit lipid A biosynthesis.
abstract: Lipid A constitutes the outer monolayer of the outer membrane of Gram-negative bacteria and is essential for bacterial growth. Synthetic antibacterials were identified that inhibit the second enzyme (a unique deacetylase) of lipid A biosynthesis. The inhibitors are chiral hydroxamic acids bearing certain hydrophobic aromatic moieties. They may bind to a metal in the active site of the deacetylase. The most potent analog (with an inhibition constant of about 50 nM) displayed a minimal inhibitory concentration of about 1 microgram per milliliter against Escherichia coli, caused three logs of bacterial killing in 4 hours, and cured mice infected with a lethal intraperitoneal dose of E. coli.
authors.affiliation: Department of Microbiology, Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: H R
authors.initials: HR
authors.lastname: Onishi
authors.forename: B A
authors.initials: BA
authors.lastname: Pelak
authors.forename: L S
authors.initials: LS
authors.lastname: Gerckens
authors.forename: L L
authors.initials: LL
authors.lastname: Silver
authors.forename: F M
authors.initials: FM
authors.lastname: Kahan
authors.forename: M H
authors.initials: MH
authors.lastname: Chen
authors.forename: A A
authors.initials: AA
authors.lastname: Patchett
authors.forename: S M
authors.initials: SM
authors.lastname: Galloway
authors.forename: S A
authors.initials: SA
authors.lastname: Hyland
authors.forename: M S
authors.initials: MS
authors.lastname: Anderson
authors.forename: C R
authors.initials: CR
authors.lastname: Raetz
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D008050:Lipid A / Q000096:biosynthesis*; D051379:Mice; D008826:Microbial Sensitivity Tests; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology; D011549:Pseudomonas / Q000187:drug effects; D012705:Serratia / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D006877:Hydroxamic Acids; C101989:L 159692; C101987:L 161240; C101988:L 573655; D008050:Lipid A; D010080:Oxazoles; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase