Marine sponges often house small molecule producing symbionts extracellularly in their mesohyl, providing the host with means of chemical defense against predation and microbial infection. Here, we report an intriguing case of chemically mediated symbiosis between the renieramycin-containing sponge Haliclona sp. and its herein discovered renieramycin producing symbiont Candidatus Endohaliclona renieramycinifaciens. Remarkably, Ca . E. renieramycinifaciens has undergone extreme genome reduction where it has lost almost all necessary elements for free living while maintaining a complex, multi-copy-plasmid encoded biosynthetic gene cluster for renieramycin biosynthesis. In return, the sponge houses Ca . E. renieramycinifaciens in previously uncharacterized cellular reservoirs (chemobacteriocytes), where it can acquire nutrients from the host and avoid bacterial competition. This relationship is highly specific to a single clade of Haliclona sponges. Our study reveals intracellular symbionts as an understudied source for defense chemicals in the oldest living metazoans, and paves the way towards discovering similar systems in other marine sponges.

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f Parthenin and parthenolide are natural products that are closely related in structure to artemisinin, which is also a sesquiterpene lactone (SQL) and one of the most important antimalarial drugs available. Parthenin, like artemisinin, has an effect on Plasmodium blood stage development. We extended the evaluation of parthenin as a potential therapeutic for the transmissible stages of Plasmodium falciparum as it transitions between human and mosquito, with the aim of gaining potential mechanistic insight into the inhibitory activity of this compound. We posited that if parthenin targets different biological pathways in the parasite, this in turn could pave the way for the development of druggable compounds that could prevent the spread of artemisinin-resistant parasites. We examined parthenin's effect on male gamete activation and the ookinete-to-oocyst transition in the mosquito as well as on stage V gametocytes that are present in peripheral blood. Parthenin arrested parasite development for each of the stages tested. The broad inhibitory properties of parthenin on the evaluated parasite stages may suggest different mechanisms of action between parthenin and artemisinin. Parthenin's cytotoxicity notwithstanding, its demonstrated activity in this study suggests that structurally related SQLs with a better safety profile deserve further exploration. We used our battery of assays to test parthenolide, which has a more compelling safety profile. Parthenolide demonstrated activity nearly identical to that of parthenin against P. falciparum, highlighting its potential as a possible transmission-blocking drug scaffold. We discuss the context of the evidence with respect to the next steps toward expanding the current antimalarial arsenal.A n estimated 198 million cases of malaria and 584,000 deaths, mostly among young children, were reported worldwide in 2013 (1). However, as a result of concerted control efforts since 2000, including antimalarial drugs, mortality has declined by 47%, resulting in an estimated 4.3 million lives saved (1). Artemisinin, delivered with a partnered drug, is one of the fastest acting antimalarial therapies available (2, 3). However, antimalarial resistance in Plasmodium falciparum has been described recently in Southeast Asia (4). This discovery emphasizes the need for novel compounds that are effective against resistant strains, presumably because they act on the parasite differently from artemisinin. Artemisinin was originally isolated from Artemisia annua, or sweet wormwood, a member of the Asteraceae family. We hypothesized that natural product compounds derived from related family members might retain potent activities against Plasmodium while targeting different biological pathways.Parthenin is a sesquiterpene lactone (SQL) derived from Parthenium hysterophorus, which is an invasive, flowering annual weed in the Asteraceae family; it grows to 2 m in height, with small white flowers, and has spread throughout much of the world (5). P. hysterophorus causes millions of dollars in damag...

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