Microbe Of The Month: Fungi to put your heart in better shape: Bernard Dixon reveals unexpected benefits in the dung of giraffes and mountain goats

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The Independent Online
Dead wood and kangaroo dung seem unpromising stuff in which to poke around for drugs to combat coronary heart disease. Yet Merck, Sharp & Dohme, a major pharmaceutical company, has found that these and other outre materials are excellent sources of such drugs because of the microbes they harbour.

Filamentous fungi, visible only under the microscope, make the newly discovered substances called zaragozic acids. The practical application of these acids could well signal a new approach to the avoidance of coronary heart disease by preventing the accumulation of the fatty deposits - atheroma - that reduces blood flow through the heart's own (coronary) arteries.

Microbes have long provided us with weapons to fight disease. Perhaps the best known are antibiotics, which are secreted by fungi and bacteria and can attack other bacteria responsible for serious infections. From the serendipitous discovery of penicillin by Alexander Fleming in 1928 and its practical development by Howard Florey, Norman Heatley and Ernst Chain a decade later, knowledge of how these 'magic bullets' actually work has understandably followed rather than preceded their discovery. Increasingly, however, scientists have sought to design and/or search for drugs on rational principles to interfere with specific features of the body or of infecting agents.

There are several risk factors for coronary heart disease, and thus several approaches to its prevention. Drugs are now widely used, for example, to reduce adversely high blood pressure. Another risk factor is too great a level of cholesterol in the bloodstream, which enhances the deposition of atheroma. This in turn raises possibilities for medical intervention, and it is here that the newly isolated fungi, which belong to a group known as ascomycetes, have a role.

Cholesterol is neither, as is sometimes suggested, wholly unwelcome nor derived solely from particular foods. The body also makes it, using it with ingested cholesterol to manufacture hormones and other essential substances. Nevertheless, excess cholesterol in the blood heightens the danger of coronary heart disease.

Some years ago, scientists at Merck Research Laboratories in New Jersey, US, together with their Merck, Sharp & Dohme colleagues in Madrid, reasoned that blood cholesterol might be reduced by interfering with the chemical transformations through which it is synthesised in the body. A particularly tempting target was the enzyme squalene synthase, which catalyses one of the reactions in the sequence. If this could be specifically inhibited, cholesterol synthesis might be impaired without any adverse effects.

Because fungi were known to make inhibitors of several other enzymes, the team initiated a search for fungi capable of impairing the activity of squalene synthase. Normally, when researchers scour the environment for microbes with potentially useful qualities, they screen soil samples - an immensely rich source of microbial life. In this case, however, the scientists decided to widen the net by obtaining a variety of other materials. They inoculated the materials into nutrient medium, isolated any fungi that grew, and tested each of them to see whether they contained a substance capable of inhibiting squalene synthase.

The first success came when they tested water from the Jalon river in the Spanish province of Zaragoza. It contained an ascomycete fungus that produced a potent inhibitor of the enzyme. In recognition of its origin, the researchers gave the name zaragozic acid to this and members of the same family of chemicals subsequently found in other ascomycetes. The fungi came from an astonishing range of materials. Among those successfully screened by the Merck team were dung from a mountain goat in Greece; a giraffe in Kenya; and an elk, a cottontail rabbit and a big-horn sheep in Arizona. Other sources the scientists have identified include bark from trees in New Zealand, the Philippines and New Jersey.

It is barely three years since the first zaragozic acid was reported in the scientific literature. Nevertheless, it is already clear that they are extremely potent inhibitors of squalene synthase. Even in very low concentrations, they not only severely impair the activity of the enzyme in human cells grown in the laboratory, but also do so when given to various animals. In theory, this indicates that they will be equally effective when used as drugs to impair cholesterol synthesis and thus prevent coronary heart disease. Further research will show whether this goal can be realised.

Meanwhile, what is the natural role of zaragozic acids? Their specificity of action, in inhibiting squalene synthase, indicates a single, defined function. Weighing against that is the widely differing array of ecological niches from which the fungi making zaragozic acids have been isolated. The fact that the acids have harmful effects on other fungi suggests that their producers secrete them into the environment for this very purpose, for defence or territorial expansion. But this argument has lost much of its force with the discovery that the zaragozic acids are not secreted but remain bound to the minuscule threads of the fungi that produce them. Time will (probably) tell.

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