Antibacterial agents that inhibit lipid A biosynthesis.
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.
Onishi
H R
HR
Department of Microbiology, Merck Research Laboratories, Rahway, NJ 07065, USA.
Pelak
B A
BA
Gerckens
L S
LS
Silver
L L
LL
Kahan
F M
FM
Chen
M H
MH
Patchett
A A
AA
Galloway
S M
SM
Hyland
S A
SA
Anderson
M S
MS
Raetz
C R
CR
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
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