Synthesis and siderophore and antibacterial activity of N5-acetyl-N5-hydroxy-L-ornithine-derived siderophore-beta-lactam conjugates: iron-transport-mediated drug delivery.
N5-Acetyl-N5-hydroxy-L-ornithyl-N5-acetyl-N5-hydroxy-L-ornithyl-N5-acety l- N5-hydroxy-L-ornithine, the functionally instrumental component of the albomycins and ferrichromes, has been incorporated as a "carrier" substructure into both carbacephalosporin and oxamazin type beta-lactam antibiotics. The previously synthesized protected version of this tripeptide (14) was coupled with various beta-lactam analogues 17, 19, 24, and 25 to give protected conjugates 21, 22, 26, and 27. Final deprotection by hydrogenolysis provided the deprotected siderophore-beta-lactam antibiotic conjugates 1-4. The growth-promoting ability of each has been evaluated using either the siderophore-deficient mutant Shigella flexneri SA 100 or S. flexneri SA240 (SA 100 iucD:Tn5). Measurement of the growth-promoting activity using two isogenic Escherichia coli strains differing only in the presence or absence of fhuA (hydroxamate ferrichrome receptor) suggests uptake by the hydroxamate iron-transport system. The antibacterial activity of these conjugates has been investigated, and the potential for use of the ferrichrome iron-transport system as a means of drug delivery is discussed.
Dolence
E K
EK
Department of Chemistry and Biochemistry, University of Notre Dame, Indiana 46556.
Minnick
A A
AA
Lin
C E
CE
Miller
M J
MJ
Payne
S M
SM
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001384:Azetidines / Q000138:chemical synthesis* / Q000494:pharmacology; D001692:Biological Transport; D002511:Cephalosporins / Q000737:chemistry; D055598:Chemical Phenomena; D002621:Chemistry; D004337:Drug Carriers; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D005291:Ferrichrome / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007769:Lactams; D015394:Molecular Structure; D009154:Mutation; D012763:Shigella flexneri / Q000187:drug effects / Q000254:growth & development; D017262:Siderophores; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D001384:Azetidines; D002511:Cephalosporins; D004337:Drug Carriers; D007502:Iron Chelating Agents; D007769:Lactams; D017262:Siderophores; D047090:beta-Lactams; C026739:carbacephems; C067820:7-((N(5)acetyl-N(5)-hydroxyornithyl-N(5)acetyl-N(5)hydroxyornithyl-N(5)-acetyl-N(5)-hydroxyornithyl-4-hydroxyphenylglycyl)amino)-3-chloro-1-carba-3-cephem-4-carboxylic acid; C067819:7-((N(5)-acetyl-N(5)-hydroxyornithyl-N(5)-acetyl-N(5)-hydroxyornithyl-N(5)-acetyl-N(5)-hydroxyornithyl-phenylglycyl)amino)-1-carba-3-chloro-3-cephem-4-carboxylic acid; D005291:Ferrichrome; C015657:albomycin; D007501:Iron