A novel prodrug of an impermeant inhibitor of 3-deoxy-D-manno-2-octulosonate cytidylyltransferase has antibacterial activity.
Although 8-amino-2,6-anhydro-3,8-dideoxy-D-glycero-D-talo-octonic acid (2) is a potent inhibitor of 3-deoxy-D-manno-octulosonate cytidylyltransferase (CMP-KDO synthetase), it is unable to reach its cytoplasmic target and is therefore inactive as an antibacterial agent. However, esterification of 2 with 8-(hydroxymethyl)-1-naphthyl methyl disulfide (8) generates a prodrug (12), which gains entry into bacterial cells. Intracellular reduction of the disulfide leads to a rapid, intramolecular, displacement of the acid 2, which then inhibits the growth of Gram-negative bacteria by interfering with the biosynthesis of lipopolysaccharide.
Norbeck
D W
DW
Anti-infective Research Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Rosenbrook
W
W
Kramer
J B
JB
Grampovnik
D J
DJ
Lartey
P A
PA
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004951:Esterification; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000187:drug effects; D013400:Sugar Acids / Q000138:chemical synthesis* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D011355:Prodrugs; D013400:Sugar Acids; C058712:(8-(methyldithio)-1-naphthyl)methyl-8-amino-2,6-anhydro-3,8-dideoxyoctonate; D009713:Nucleotidyltransferases; C028984:3-deoxy-manno-octulosonate cytidyltransferase