Design and synthesis of peptide derivatives of a 3-deoxy-D-manno-2-octulosonic acid (KDO) analogue as novel antibacterial agents acting upon lipopolysaccharide biosynthesis.
On the basis of the knowledge that the amino acid 3 (8-amino-2,6-anhydro-3,8-dideoxy-D-glycero-D-talo-octonic acid) is a potent inhibitor of 3-deoxy-manno-octulosonate cytidylyltransferase, attempts were made to design derivatives that would act as antibacterials against Gram-negative bacteria by inhibiting lipopolysaccharide biosynthesis. Compound 3 and the derivatives 15 and 16 containing an additional amino acid were not lethal to bacteria. However, compounds 17-22, which contain a N-terminally linked dipeptide, exhibited good antibacterial activity in vitro on testing against strains of the Gram-negative bacteria Escherichia coli and Salmonella typhimurium. They have no activity against Gram-positive bacteria such as Staphylococcus aureus.
Claesson
A
A
Department of Antibacterial Chemotherapy, Research and Development, Astra Alab, Södertälje, Sweden.
Jansson
A M
AM
Pring
B G
BG
Hammond
S M
SM
Ekström
B
B
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D001419:Bacteria / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D013400:Sugar Acids / Q000138:chemical synthesis* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; D013400:Sugar Acids; C002532:2-keto-3-deoxyoctonate