Synthesis and in vitro antibacterial activity of spermidine-based mixed catechol- and hydroxamate-containing siderophore--vancomycin conjugates.
The first antibiotic conjugates of vancomycin (1) and siderophore analogues containing spermidine-based catechol ligands (conjugate 11) as well as mixed catechol and hydroxamate ligands (conjugate 13) are described. The design of the conjugates was based on the earlier observation that conjugation of siderophore components to beta-lactam antibiotics induced active iron transport-mediated drug delivery. The novel conjugates (11 and 13) were synthesized by selective acylation of the primary amino group of 1. Preliminary biological studies indicated that siderophore modified vancomycins lost some activity (4- to 16-fold) against Gram-positive bacteria relative to vancomycin itself, and were generally similar to vancomycin in activity against Gram-negative bacteria under iron-sufficient conditions. However, under iron-depleted conditions which mimic human serum, conjugate 11 displayed enhanced antibacterial activity against an antibiotic hypersensitive strain of Pseudomonas aeruginosa.
Ghosh
M
M
Department of Chemistry and Biochemistry, University of Notre Dame, IN 46556, USA.
Miller
M J
MJ
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D002396:Catechols / Q000737:chemistry; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects; D006877:Hydroxamic Acids / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D016982:Micrococcus luteus / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D017262:Siderophores / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013095:Spermidine / Q000031:analogs & derivatives / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D002396:Catechols; D006877:Hydroxamic Acids; D017262:Siderophores; D014640:Vancomycin; C034221:catechol; D013095:Spermidine