Accumulation of incomplete metabolic side products of lipid A in Salmonella typhimurium during inhibition of 3-deoxy-D-manno-octulosonate incorporation by a new class of antibacterial agents.
A new class of antibacterial agents for Gram-negative bacteria, rationally designed to inhibit the incorporation of 3-deoxy-D-manno-octulosonate into lipopolysaccharide (LPS), was recently reported. In Salmonella typhimurium, where the lipid A species are well characterised, it was previously demonstrated that the addition of a compound which inhibits the enzyme 3-deoxy-manno-octulosonate cytidylytransferase (CMP-KDO synthetase; EC 2.7.7.38) leads to rapid accumulation of lipid A derivatives. The major lipid A species, IVA (O-(2-amino-2-deoxy-beta-D-glucopyranosyl)-(1-6)-2-amino-2-deoxy-alpha-D - glucose, acylated at positions 2, 3, 2', 3' with beta-hydroxymyristoyl groups and bearing phosphates at positions 1 and 4'), was shown to be converted mainly to LPS by pulse-chase experiments in the absence of inhibitor. Labelled precursor (IVA) was also chased to other more polar lipid A derivatives. During chase in the presence of inhibitor, there was no conversion to LPS, while the major lipid A species was converted to the same polar lipid A derivatives as in chase without inhibitor. Our data indicate that despite the accumulation of several species of lipid A derivatives during inhibition of LPS synthesis, only IVA is destined for synthesis of mature LPS when LPS synthesis resumes. The more polar lipid A derivatives would thus represent aberrant side reaction products which occur when the pathway is inhibited.
Kadam
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SK
Anti-infective Research Division, Abbott Laboratories, Abbott Park, IL 60064.
Doran
C C
CC
Goldman
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RC
D000606:Amino Sugars / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000145:classification / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000378:metabolism; D008050:Lipid A / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000096:biosynthesis; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000187:drug effects / Q000378:metabolism*; D013400:Sugar Acids / Q000378:metabolism* / Q000494:pharmacology*
D000606:Amino Sugars; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008050:Lipid A; D008070:Lipopolysaccharides; D011355:Prodrugs; D013400:Sugar Acids; C053472:(1,5-anhydro-7-amino-2,7-dideoxyheptopyranosyl)carboxylate; C002532:2-keto-3-deoxyoctonate; D009713:Nucleotidyltransferases; C028984:3-deoxy-manno-octulosonate cytidyltransferase