Anti-malarials from seaweed: a tale of two pathogens, and one very nifty chemical.

This morning I went to a seminar given by Prof. Julia Kubanek from the University of British Columbia, entitled "Antifungal chemical cues in marine algae and their future in drug discovery".

It was excellent. It was excellent because it told a story, and an unlikely story at that.

In the coral reefs off Fiji, there lives a red seaweed named Callophycus serratus. Not only is it very pretty, but it's also fairly rare, with its geographic distribution limited to the South Pacific Ocean.

But it wasn't the prettiness or rarity of C. serratus that interested Julia and her team, who were investigating antimicrobial defence compounds produced by organisms in coral reefs. What caught their attention was its cleanliness. The fronds of the algae were free from bacterial biofilms, slime moulds and other microbial disease agents, including Lindra thalassia, a common ascomycete fungal pathogen of sea grass. C. serratus clearly had a few tricks up its sleeve when it came to evading infection, and the researchers wanted to learn these tricks.

Callophycus serratus [source]

They discovered that the seaweed was producing a family of antimicrobial chemicals called bromophycolides, which accumulate around wounds on the surface of the algae, acting as a 'chemical band-aid' to prevent invasion of the wound site by microbial pathogens such as L. thalassia. Of these, Bromophycolide A appeared to be the most abundant in the algal tissue, and the most potent in its activity against L. thalassia.

[source]

Needless to say, as an agricultural pathologist I wondered what the effects of these bromophycolides on fungal crop pathogens might be. As it turns out, they weren't particularly impressive; while Bromophycolide A did inhibit the growth of the wheat leaf blotch pathogen Septoria tritici, it took very high doses of the chemical to do so. Results from the other two crop pathogens tested were equally unimpressive, and I slumped back in my chair, disappointed at these findings, and that my own beloved wheat pathogen Fusarium  hadn't been investigated.

But this is where the story takes a sudden turn, a twist that had me shake off my grumps and sit back up in my seat. Because while the effects of bromophycolides on fungal plant pathogens were yawn worthy, their effects on human pathogens, namely the malarial parasite Plasmodium falcifarum, had me wide awake.

Despite having been isolated from a marine plant species, due to its role in defence against a marine plant fungus, Bromophycolide A is able to kill a P. falcifarum, a human red blood cell parasite completely unrelated to its natural target, even when applied to infected blood samples at micromolar levels. The researchers found that it does this in the same way that conventional quinine based anti-malarial drugs do:

In order to replicate, P. falcifarum invades a red blood cell, and sets up camp, consuming the cell's haemoglobin to give it energy for replication. The problem is that the core of the haemoglobin molecule, haem, is toxic to the parasite, so they bundle it up into a crystal structure called hemozoin, where it can do no harm. Both conventional quinine based anti-malarial drugs and bromophycolides prevent the formation of hemozoin, exposing the parasite to toxic haem. The difference is that while some malarial parasites have evolved mechanisms to pump the quinine compounds out of the blood cell, they have no such strategy for avoiding the effects of bromophycolides.

While Bromophycolide A seems a promising new candidate for anti-malarial drug development, there are a few obstacles still to be crossed. These include the challenge of synthesising the drug from scratch, in order for it to be mass produced, and finding a way to prevent it being metabolised (broken down) by the mammalian body before it has chance to kill off the malarial parasite. Even so, with resistance to existing anti-malarial drugs developing and spreading with alarming speed and frequency, these obstacles are ones worth crossing.

I don't know what made Julia and her team think to look at the effects of an anti-fungal marine plant compound on a terrestrial mammalian parasite. It's likely that the mechanism by which bromophycolide A limits P. falcifarum growth is completely different to the way it prevents infection of C. serrata  by marine fungi, making its limiting effects on the growth of both pathogens all the more improbable and amazing. As a young scientist who also looks at plant defence mechanisms against disease, I find this story inspirational and encouraging, and a reminder to think outside the box. It's also a reminder of the wealth and value of marine ecoysystems, and the ways in which their protection may benefit our own species.