W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Department of Chemistry, Johns Hopkins University, Baltimore, MD, USA.
Sci Rep. 2018 Apr 18;8(1):6176. doi: 10.1038/s41598-018-24296-0.
The Chromobacterium sp. Panama bacterium has in vivo and in vitro anti-Plasmodium properties. To assess the nature of the Chromobacterium-produced anti-Plasmodium factors, chemical partition was conducted by bioassay-guided fractionation where different fractions were assayed for activity against asexual stages of P. falciparum. The isolated compounds were further partitioned by reversed-phase FPLC followed by size-exclusion chromatography; high resolution UPLC and ESI/MS data were then collected and revealed that the most active fraction contained a cyclic depsipeptide, which was identified as romidepsin. A pure sample of this FDA-approved HDAC inhibitor allowed us to independently verify this finding, and establish that romidepsin also has potent effect against mosquito stages of the parasite's life cycle. Genomic comparisons between C. sp. Panama and multiple species within the Chromobacterium genus further demonstrated a correlation between presence of the gene cluster responsible for romidepsin production and effective antiplasmodial activity. A romidepsin-null Chromobacterium spp. mutant loses its anti-Plasmodium properties by losing the ability to inhibit P. falciparum HDAC activity, and romidepsin is active against resistant parasites to commonly deployed antimalarials. This independent mode of action substantiates exploring a chromobacteria-based approach for malaria transmission-blocking.
巴拿马色杆菌具有体内和体外抗疟原虫的特性。为了评估色杆菌产生的抗疟原虫因子的性质，采用生物测定指导的分组进行了化学分组，对不同的分组进行了抗疟原虫无性阶段的活性测定。分离出的化合物进一步通过反相 FPLC 进行分配，然后通过尺寸排阻色谱进行分配；收集并分析了高分辨率 UPLC 和 ESI/MS 数据，结果表明最活跃的部分含有一种环状脂肽，被鉴定为罗米地辛。该 FDA 批准的 HDAC 抑制剂的纯样品使我们能够独立验证这一发现，并确定罗米地辛对寄生虫生命周期的蚊子阶段也具有很强的作用。色杆菌属的多个种与巴拿马色杆菌之间的基因组比较进一步表明，负责罗米地辛产生的基因簇的存在与有效的抗疟原虫活性之间存在相关性。缺乏罗米地辛的色杆菌突变体由于丧失了抑制疟原虫 HDAC 活性的能力而失去了抗疟原虫的特性，并且罗米地辛对常用抗疟药物有抗药性的寄生虫也有活性。这种独立的作用模式证实了探索基于色杆菌的疟疾传播阻断方法的合理性。
