Chemical synthesis and biological evaluation of gallidermin-siderophore conjugates
Chemical synthesis and biological evaluation of gallidermin-siderophore conjugates
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DOI：
10.1039/c0ob00846j
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发表时间：
2011-01-01
影响因子：
3.2
通讯作者：
Vederas, John C.
中科院分区：
文献类型：
--
作者：
Yoganathan, Sabesan;Sit, Clarissa S.;Vederas, John C.
lantibiotic gallidermin在赖氨酸残基处通过绿脓菌螯铁蛋白、agrobactin和去铁胺B的衍生物的区域选择性连接进行修饰，目的是使革兰氏阴性菌的铁载体受体将抗生素-铁螯合剂缀合物转运通过外膜。所有的缀合物都保留了对革兰氏阳性指示菌株乳酸乳球菌乳酸亚种的活性。[医]山柑然而，针对几种革兰氏阴性菌株的缀合物的测试产生了意想不到的结果。用100 μ M与Fe 3+络合的缀合物处理的细菌比在无铁培养基中生长的细菌生长得更好，但比在补充有10 μ M FeCl 3的相同培养基中生长的细菌更差。尽管这些发现表明缀合物不能抑制革兰氏阴性细菌的生长，但它们表明外膜的渗透，并为其他lantibiotic缀合物的设计提供结构-活性信息。该合成策略适用于将生物标志物或荧光探针连接到gallidermin，以研究其定位和作用方式。由于有许多羊毛硫抗生素以未知的作用机制起作用，因此这种化学方法提供了一种用生物标志物修饰此类肽以用于生物学研究的方法。
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. cremoris HP. However, testing of the conjugates against several Gram-negative strains yielded unexpected results. Bacteria treated with 100 mu M 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 mu M 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.