Theriault Jimmy R., Wurst Jacqueline, Jewett Ivan, Verplank Lynn, Perez Jose R., Gulick Andrew M., Drake Eric J., Palmer Michelle, Moskowitz Sam, Dasgupta Nandini, Brannon Mark K., Dandapani Sivaraman, Munoz Ben, Schreiber Stuart
The Broad Institute Probe Development Center, Cambridge, MA
Hauptman-Woodward Medical Research Institute, State University of New York, Buffalo, NY
The bacteria produces a peptide siderophore known as pyoverdine, which has a great affinity for iron and is used to acquire iron from the external environment. Several enzymes such as the PvdQ acylase are required for the biosynthesis of pyoverdine. Deletion of the PvdQ gene disrupts pyoverdine production and hinders proliferation. Bacteria defective in pyoverdine synthesis are not infectious implying that disrupting this siderophore production through PvdQ inhibition could be exploited as a putative target for the development of novel antibiotic compounds. This report describes the development of a small molecule inhibitor (ML318, CID 56604881) of PvdQ acylase. ML318 inhibits PvdQ with an IC of 6 nM, has no apparent toxicity in mammalian HeLa cells up to a concentration of 100 μM, and inhibits growth and pyoverdine production in exposed to iron-limiting conditions with an IC < 50 μM. ML318 can also significantly reduce the intracellular uptake of iron inside the bacteria. This probe is a useful tool for ongoing characterization of pyoverdine’s role in biology and could serve as a starting point for the development of a novel antibiotic.
这种细菌产生一种名为绿脓菌素的肽类铁载体，它对铁具有很强的亲和力，用于从外部环境获取铁。绿脓菌素的生物合成需要几种酶，如PvdQ酰基转移酶。PvdQ基因的缺失会破坏绿脓菌素的产生并阻碍细菌增殖。绿脓菌素合成有缺陷的细菌没有传染性，这意味着通过抑制PvdQ来破坏这种铁载体的产生可作为开发新型抗生素化合物的一个假定靶点。本报告描述了一种PvdQ酰基转移酶的小分子抑制剂（ML318，化合物标识符56604881）的研发情况。ML318抑制PvdQ的半数抑制浓度为6 nM，在浓度高达100 μM时对哺乳动物HeLa细胞无明显毒性，并且在暴露于铁限制条件下时，以小于50 μM的半数抑制浓度抑制细菌生长和绿脓菌素的产生。ML318还能显著降低细菌内铁的细胞内摄取。该探针是持续表征绿脓菌素在生物学中的作用的有用工具，可作为新型抗生素开发的起点。
