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

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.

Aedes spp. and Their Microbiota: A Review

“…The Gram-negative Chromobacterium inhibits growth of other bacteria in the midgut, displays entomopathogenic activity on larvae and adults, and was suggested to exert in vitro and in vivo anti-pathogen activity through stable secondary metabolites. While romidepsin appeared to be the most likely Chromobacterium -produced metabolite responsible for antiplasmodial activity (Saraiva et al, 2018b), the anti-DENV activity is mediated by an aminopeptidase interfering with DENV-2 attachment by promoting the degradation of the Flavivirus E protein (Saraiva et al, 2018a). These effects on mosquitoes, together with its culturability, make Chromobacterium an ideal candidate to be integrated in strategies for controlling both mosquito populations and pathogen transmission.…”

“…aegypti , it negatively impacts mosquito vector competence to dengue viruses (Saridaki and Bourtzis, 2010; Mohanty et al, 2016; O’Neill, 2018). Additional strategies aim at identifying natural symbionts of mosquitoes and either alter them genetically to express anti-pathogen effectors or disrupt their natural symbiosis with the insect host (Coutinho-Abreu et al, 2010; Ramirez et al, 2014; Kean et al, 2015; Saraiva et al, 2018a, b).…”

Thermal stress responses of Sodalis glossinidius, an indigenous bacterial symbiont of hematophagous tsetse flies

“…While these theories have never been experimentally proven, they are correlatively validated by the fact that Sodalis density positively correlates with trypanosome infection prevalence (16, 19, 63). Finally, symbiotic bacteria from the genera Kosakonia and Chromobacterium , which are found naturally in the midgut of Anopheles gambiae and Aedes aegypti mosquitoes, produce and secrete reactive oxygen intermediates (64), histone deacetylases (65) and aminopeptidases (66) that exert direct anti- Plasmodium and anti-dengue activity.…”

Natural Products: A Potential Source of Malaria Transmission Blocking Drugs?

“…stephensi mosquito midguts as well as reducing the number of sporozoites per mosquito [59]. Dactinomycin (a known transcription inhibitor in eukaryotic cells) and romidepsin (histone deacetylase inhibitor) [49] both show sub-micromolar gametocytocidal activity ( Figure 2, Table 1), with in vivo transmission-blocking activity only confirmed for romidepsin [60]. Although these oligopeptides do show potency, their large MW and poor solubility detracts from their development as TCP-5 candidates.…”