Chromobacterium spp. mediate their anti-Plasmodium activity through secretion of the histone deacetylase inhibitor romidepsin

Raúl G. Saraiva, Callie R. Huitt-Roehl, Abhai Tripathi, Yi Qiang Cheng, Jürgen Bosch, Craig A. Townsend, George Dimopoulos

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number6176
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - 1 Dec 2018

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Chromobacterium
histone deacetylase
Plasmodium
secretion
antimalarials
Plasmodium falciparum
Panama
depsipeptides
parasites
multigene family
malaria
life cycle (organisms)
mechanism of action
fractionation
Culicidae
bioassays
genomics
mutants
bacteria

Cite this

Saraiva, Raúl G. ; Huitt-Roehl, Callie R. ; Tripathi, Abhai ; Cheng, Yi Qiang ; Bosch, Jürgen ; Townsend, Craig A. ; Dimopoulos, George. / Chromobacterium spp. mediate their anti-Plasmodium activity through secretion of the histone deacetylase inhibitor romidepsin. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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abstract = "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.",
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Chromobacterium spp. mediate their anti-Plasmodium activity through secretion of the histone deacetylase inhibitor romidepsin. / Saraiva, Raúl G.; Huitt-Roehl, Callie R.; Tripathi, Abhai; Cheng, Yi Qiang; Bosch, Jürgen; Townsend, Craig A.; Dimopoulos, George.

In: Scientific Reports, Vol. 8, No. 1, 6176, 01.12.2018.

Research output: Contribution to journalArticle

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