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NySTatin

An Essay

Nystatin is the name given to the first antifungal antibiotic found to be safe and effective in the treatment of human disease. The compound was discovered by a New York scientist, Elizabeth Hazen, who, with Rachel Brown, went on to elucidate the structure and activity of the compound. This essay outlines their fascinating story.

Because of the work of Alexander Fleming and Howard Florey, the search for antibacterial agents had reached the point by 1950 where potentially new compounds were being discovered in microbes extracted from soil. Streptomyces, for instance, had yielded the important antibiotic streptomycin (1943). Actinomyces from soil were generally found to yield relatively high concentrations of a range of different toxins. Bacteria were the usual target for these screening processes. However, once bacterial disease had been suppressed, it became clear that fungi were also important causes of disease. In 1945, no antifungal agents were available to treat fungal disease.

Elizabeth Hazen, of the New York State Department of Health, initiated a screening program for antifungal agents from microbes isolated from soil. She used the fungi Cryptococcus neoformans and Candida albicans as targets in her bioassays. These fungi were at the time important pathogens becoming increasingly apparent in patients who had been treated with antibiotics that suppressed bacterial competitors. LINK

Microbial isolates were grown in either static or shaken liquid culture by Elizabeth Hazen. The bulk extract was placed against the bioassay fungi. Where activity was observed, the process of identifying and characterising the active component commenced. The organic chemist, Rachel Brown extracted compounds from solution and the bulk organism, and fractionated the components. These extracts would then be returned and tested in the bioassay. Some cultures resulted in more than one active ingredient, and sometimes the active component was found in broth and solid materials. Some fractions proved to be toxic, but on purification were found with quite different properties (solubility in water, activity against the bioassays etc). Once active compounds had been found, they were tested for toxicity against laboratory animals.

Using this slow and cyclical process, an interesting compound was found in 1948. The compound came from Streptomyces noursei, a newly discovered actinomycete. Ultimately named nystatin, it was to then pass through a series of processes to first provide enough material to test in humans, and then bulk up for industrial production.

Nystatin is relatively insoluble. It can, therefore, be applied superficially, or taken orally for intestinal complaints. It has also been used successfully elsewhere: to protect paintings after inundation, and in plant pathology. Nystatin is similar in structure to amphotericin B, both being polyenes. LINK However, amphotericin B is much more soluble and can therefore be injected for treatment of deep tissue mycoses.

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