Many microorganisms indigenous to the soil, especially actinomycete bacteria and many fungi, produce biologically active secondary metabolites. Intensive screening of culture supernatants (usually called “fermentation broths”), rich in secondary metabolites, has led to the discovery of numerous clinically valuable antibiotics, with penicillin as the most famous example, but of many other types of valuable compounds as well. The structures of newly characterized compounds with herbicidal, insecticidal, and nematocidal activities from soil microorganisms are described in the scientific literature at a rate of several hundred each year.

The avermectins were discovered in the early 1980s as a result of a deliberate search for antihelminthic compounds produced by soil microorganisms. Helminths are parasitic worms that infect the intestines of any animal unfortunate enough to ingest their eggs. There were two particularly notable features of the screening program. First, the microbial fer mentation broths were tested by being administered in the diet to mice infested with the nematode Nematospiroides dubius. Nematodes are a sub class of helminths that includes roundworms or threadworms. Although such an in vivo assay was expensive, it simultaneously tested for efficacy of the preparation against the nematode and toxicity to the host. Second, to increase the chance of discovering new types of compounds, the selection of microorganisms for testing was biased toward those with unusual morpho logical traits and nutritional requirements. The morphological characteristics of Streptomyces avermitilis, the producer of avermectins, were unlike those of other known Streptomyces species. S. avermitilis produces a family of closely related macrocyclic lactones (Figure 1), compounds that are active against certain nematodes and arthropods at extremely low doses, but have relatively low toxicity to mammals. These avermectins and their derivatives, as the compounds came to be called, are highly effective in veterinary use and in treating infestations in humans.

Fig1. Avermectin B1. This compound is the major macrocyclic lactone produced by Streptomyces avermitilis. Ivermectin is a synthetic derivative of avermectin B1.

Avermectins act on invertebrates by activating glutamate-gated chloride channels in their nerves and muscles, disrupting pharyngeal function and locomotion. The paralyzed parasite most likely starves to death. Their selective toxicity–they do not harm vertebrates–has led to the conclusion that avermectins affect a specific cellular target either absent or inaccessible in the resistant organisms. The avermectins do not migrate in soils from the site of application and are subject to both rapid photodegradation and microbial decomposition. Consequently, avermectins are not expected to persist for a long time in the feces of treated animals.The biological activity and selective toxicity of the avermectins could not have been anticipated even if the structures of these compounds had been known.

The structure of a naturally occurring small molecule with desirable biological activity is generally used as the starting point for the design and preparation of semisynthetic derivatives with improved activity, selectivity, and stability characteristics. This has proved to be the case for avermectins. Ivermectin (IVM; 22,23-dihydroavermectin B1a, Figure 1), a semisynthetic derivative of avermectin B1a, is an indispensable drug in mass treatment programs to eradicate two widespread serious diseases that affect millions of people and that are caused by nematodes: river blindness (onchocerciasis) and lymphatic filariasis (Box 1).

Table1. Bacterial and fungal secondary metabolites.