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Antibiotics changed medicine in the 1940s, but they left a gap. As the National Inventors Hall of Fame explains, broad-spectrum antibiotics killed so many kinds of bacteria that none were left to keep fungi under control, so fungal infections followed. Two scientists at the New York State Department of Health, one in New York City and one in Albany, closed part of that gap using the post office as their lab bench. This post covers who they were, how they found nystatin, how it works and what their method teaches.
Who were Elizabeth Hazen and Rachel Brown?
The National Inventors Hall of Fame entry for Elizabeth Lee Hazen records that she was born on 24 August 1885 in Rich, Mississippi, lost both parents by the age of 3, and went to a one-room school. After a degree in 1910 she taught high school physics and biology, then earned a master's in biology at Columbia University in 1917 and a doctorate in microbiology in 1927, as one of Columbia's first women doctoral students. In 1931 she joined the New York State Department of Health in New York City, and in 1944 she was asked to lead work on fungi.
The entry for Rachel Fuller Brown records that she was born on 23 November 1898 in Springfield, Massachusetts. A friend of her grandmother paid for her studies at Mount Holyoke College, where she took a degree in history and chemistry in 1920. She earned a master's in chemistry at the University of Chicago in 1921 and a doctorate in chemistry and bacteriology there in 1933. At the Department of Health's laboratories in Albany she developed a faster syphilis test and antiserums for pneumonia types.
How did they find nystatin by post?
By 1948 Hazen had found new antifungal agents among the actinomycetes, filamentous soil bacteria, using a soil-sampling technique established by Selman Waksman (read about him in our post on Waksman and streptomycin). The head of the division, Gilbert Dalldorf, asked Brown, a chemist, to help.
The division of labour was clear:
In New York City, Hazen grew organisms from soil samples and tested them against two disease-causing fungi, Candida albicans and Cryptococcus neoformans.
Whenever a culture killed the fungi, she mailed it to Brown in Albany in a jar.
Brown extracted the active substance and sent it back for testing.
At first every agent that killed the fungi was also highly toxic to animals. Then a culture from the soil of a garden belonging to Hazen's friend Walter B. Nourse looked promising. Hazen named the organism Streptomyces noursei after him, and the drug was named nystatin after the New York State Department of Health.
What did their first paper report?
In Proceedings of the Society for Experimental Biology and Medicine (1951), Hazen and Brown reported two antibiotics from the same soil actinomycete. One was released outside the cells and resembled a known compound, actidione. The other, which they called fungicidin and which became nystatin, stayed inside the cells, stopped fungal growth and killed fungi, and apparently had no antibacterial action. It appeared useful against histoplasmosis and cryptococcosis in mice. A 1953 paper in Science tested it in mice given lethal mixtures of the antibiotic aureomycin and Candida albicans, exactly the problem broad-spectrum antibiotics created.
The 1951 paper also gave a measure of toxicity: the approximate LD50 of crude fungicidin injected into the abdomen of mice was 20 to 26 mg per kg of body mass. LD50 is the dose that kills half the animals tested.
Worked example. For a sample mouse of mass 25 g:
Convert to kilograms: 25 g = 0.025 kg.
Lower end: 20 mg/kg × 0.025 kg = 0.5 mg.
Upper end: 26 mg/kg × 0.025 kg = 0.65 mg.
So the LD50 for that mouse is about 0.5 to 0.65 mg. The common mistake is to forget the conversion and multiply by 25, which gives an answer a thousand times too large. The paper also noted that injection under the skin was considerably less toxic, so the route of a dose matters as much as its size.
How does nystatin kill fungi?
Nystatin belongs to the polyene antifungals. The NIH's LiverTox summary of antifungal agents explains that polyenes bind to ergosterol in the fungal cell membrane, making the membrane more permeable until the cell breaks down. A 1986 review in Biochimica et Biophysica Acta notes that fungal membranes contain ergosterol while human membranes contain cholesterol, which is generally taken as the basis of the drug's selectivity, though the review adds that lab studies have not always borne this out.
If cell membranes and fungal cell structure feel rusty, our guide to Kingdom Fungi covers the biology.
What happened to nystatin after the discovery?
According to the Hall of Fame, nystatin was introduced in 1954 after approval by the US Food and Drug Administration and patented in 1957 (US Patent 2,797,183). E. R. Squibb bought the rights. Hazen and Brown gave their royalties, more than 13 million dollars, to science through the non-profit Research Corporation, and in 1975 they became the first women to receive the Chemical Pioneer Award of the American Institute of Chemists.
It is still in use. The NHS page on nystatin lists it for oral thrush and skin infections caused by a fungus or yeast, available only on prescription. For any infection, ask a doctor rather than treating yourself.
What can a student take from how they worked?
Hazen and Brown split a problem by skill, kept testing through many toxic failures, and gave their reward back to research. For your own work, try one of their habits: when a problem has two parts, such as identifying an unknown salt and then writing its reactions, do each part as a separate step with its own check.
If a concept in microbiology or chemistry keeps tripping you up, the Fermi Concept Library covers every concept in physics, chemistry, biology, mathematics and computing, so you can revise the one idea that is blocking you.
Try it now: work out the LD50 range for a sample 30 g mouse from the 1951 figures, and check your units at each step.
