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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.
Highlights
In spite of remarkable progress toward its elimination throughout the last decade, malaria remains endemic in 91 countries, with nearly half of the world’s population at risk in 2016 (212,000,000 new cases and 429,000 deaths estimated in 2015)[1]
We combine in silico, in vitro and in vivo approaches to compare the anti-Plasmodium activity of a multitude of Chromobacterium species to conclude that romidepsin, a known histone deacetylase (HDAC) inhibitor, is responsible for the previously observed anti-Plasmodium activity
Given the results presented far, it is expected that a romidepsin-positive culture supernatant extract of wildtype C. sp. 968 possesses inhibitory activity against Plasmodium HDACs, the contrary being true for a romidepsin-negative extract of its ΔdepA mutant
Summary
In spite of remarkable progress toward its elimination throughout the last decade, malaria remains endemic in 91 countries, with nearly half of the world’s population at risk in 2016 (212,000,000 new cases and 429,000 deaths estimated in 2015)[1]. Notable for inducing lethality in larvae and adult Aedes and Anopheles mosquitoes, as well as in vitro and in vivo antipathogenic activity against the malaria parasite and the dengue virus[12] These properties render this bacterium an interesting candidate to control both mosquito populations and pathogen transmission, since manipulation of mosquito gut microbiota has proven successful through exposing mosquitoes to bacteria-spiked artificial nectars[13]. Panama was found to render Anopheles gambiae more resistant to malaria parasite infection when laboratory-reared mosquitoes were colonized by the bacterium prior to feeding on infectious blood[12] This anti-Plasmodium activity was proven to be mediated by bacteria-produced and secreted metabolites, as in vitro assays independent of the mosquito system showed potent activity against asexual and sexual (both gametocytes and ookinetes) stages of the parasite[12]. Romidepsin had already been shown to negatively impact P. falciparum asexual[14,15] and sexual[16] stages in vitro; here we further analyze the spectrum of this activity to include mosquito stages of the parasite and discuss potential applications of this discovery
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