Synthesis and biological evaluation of new citrate-based siderophores as potential probes for the mechanism of iron uptake in mycobacteria.
Several iron chelators containing alpha,beta-unsaturated hydroxamic acid motifs appended to a citric acid platform were synthesized. Mycobacterium paratuberculosis was then challenged to grow in the presence of a panel of siderophores (mycobactin J, deferrioxamine B, acinetoferrin, and nannochelin A) and the new synthetic agents. Of the structures tested, those containing the trans 2-octenoyl motif were preferred over those with trans cinnamoyl groups. In addition, derivatives containing longer tether lengths between the iron binding ligands (C5) were more efficacious and led to higher growth index values. Perhaps most remarkable was the finding that at 2.4 microM a trans 2-octenoylated, citrate-containing imide 6 was nearly 5-fold more effective in stimulating growth than the native chelator, mycobactin J. In this regard, new structural elements were identified (e.g., an imide motif or 2-octenoyl side chain), whose presence stimulated mycobacterial growth.
Guo
Hongyan
H
Center for Discovery of Drugs and Diagnostics, Department of Chemistry, University of Central Florida, Orlando, FL 32816-2366, USA.
Naser
Saleh A
SA
Ghobrial
George
G
Phanstiel
Otto
O
D002951:Citrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016927:Mycobacterium avium subsp. paratuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D017262:Siderophores / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D002951:Citrates; D006877:Hydroxamic Acids; D007502:Iron Chelating Agents; D017262:Siderophores; C455281:acinetoferrin imide; D007501:Iron