Chemical synthesis and biological evaluation of gallidermin-siderophore conjugates

Organic & Biomolecular Chemistry Pub Date: 2011-02-03 DOI: 10.1039/C0OB00846J

Abstract

The lantibiotic gallidermin was modified at lysine residues by regioselective attachment of derivatives of pyochelin, agrobactin and desferrioxamine B with the objective of having siderophore receptors of Gram-negative bacteria transport the antibiotic-iron chelator conjugate through the outer membrane. All of the conjugates retained activity against the Gram-positive indicator strain, Lactococcus lactis subsp. cremorisHP. However, testing of the conjugates against several Gram-negative strains yielded unexpected results. Bacteria treated with 100 μM of the conjugates complexed with Fe3+ grew better than bacteria grown in iron-free media but worse than bacteria grown in the same media supplemented with 10 μM FeCl3. Although these findings indicate that the conjugates are unable to inhibit the growth of Gram-negative bacteria, they indicate penetration of the outer membrane and provide structure–activity information for design of other lantibiotic conjugates. The synthetic strategy is applicable for linking biomarkers or fluorescence probes to gallidermin for studies on its localization and mode of action. As there are many lantibiotics that operate with unknown mechanisms of action, this chemical approach provides a means to modify such peptides with biomarkers for biological investigations.

Graphical abstract: Chemical synthesis and biological evaluation of gallidermin-siderophore conjugates
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