New synthetic siderophores and their beta-lactam conjugates based on diamino acids and dipeptides.
Linking of siderophores to antibiotics improves the penetration and therefore increases the antibacterial activity of the antibiotics. We synthesized the acylated catecholates and hydroxamates as siderophore components for antibiotic conjugates to reduce side effects of unprotected catecholate and hydroxamate moieties. In this paper, we report on bis- and tris-catecholates and mixed catecholate hydroxamates based on diamino acids or dipeptides. These compounds were active as siderophores in a growth promotion assay under iron limitation. Most of the conjugates with beta-lactams showed high in vitro activity against Gram-negative bacteria especially Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and Stenotrophomonas maltophilia. The compounds with enhanced antibacterial activity use active iron uptake routes to penetrate the bacterial outer membrane barrier, demonstrated by assays with mutants deficient in components of the iron transport system. Correlation between chemical structure and biological activity was studied.
Wittmann
S
S
Hans Knöll Institute for Natural Product Research, Jena, Beutenbergstrasse 11, D-07745, Jena, Germany.
Schnabelrauch
M
M
Scherlitz-Hofmann
I
I
Möllmann
U
U
Ankel-Fuchs
D
D
Heinisch
L
L
D000599:Amino Acids, Diamino / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002396:Catechols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004151:Dipeptides / Q000737:chemistry*; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000254:growth & development; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000254:growth & development; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D017262:Siderophores / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000599:Amino Acids, Diamino; D000900:Anti-Bacterial Agents; D002396:Catechols; D004151:Dipeptides; D006877:Hydroxamic Acids; D017262:Siderophores; D047090:beta-Lactams