Penicillin: An arms race against bacteria begins

Today, most people don’t have to worry about developing a lethal infection from a tiny cut, but up until the early 20th century, infection was a severe health problem. It was not until a fateful observation in 1928 that scientists could begin a full-scale defensive campaign against bacteria. On Sept. 28 of that year, Alexander Fleming noticed that a mold growing on an old Petri dish appeared to stop the growth of bacterial colonies. He hypothesized that the mold, Penicillium notatum, was producing a substance that could kill bacteria without harming humans, and if he could purify a sample, perhaps the substance could help stave off infections and save lives. Twelve years later at Oxford University, other scientists capitalized upon Fleming’s work, growing penicillin in massive quantities. Their efforts were hastened by the advent of World War II and the dire need for a compound that could save wounded soldiers.

The researchers discovered that the Penicillium mold grew best in a nutrient-rich broth with lots of fresh air. At facilities in the United States, they pumped air into deep fermentation tanks to help the mold grow faster. The researchers also discovered that they could use corn-steep liquor to keep the mold well nourished. However, in order to produce enough medicine to meet the needs of the war, researchers needed a strain of the mold that would grow rapidly in laboratory conditions. Army pilots sent in soil samples from all over the world containing the mold, but the most efficient strain had a humble beginning: when researchers used a strain found on a moldy cantaloupe from a local market in Peoria, IL, they doubled penicillin production. So thanks in part to an old Petri dish, corn-steep liquor, and a moldy cantaloupe, penicillin was born.

But penicillin’s omnipotence did not last long. Only five years after doctors began treating patients with the drug, 50 percent of the strains of the bug that causes staph infections (Staphylococcus aureus) were resistant to penicillin. Penicillin disarms bacteria by preventing bacterial cells from forming new cell walls. Without this ability, bacteria cannot multiply. However, some bacteria evolved ways of disarming penicillin –- for instance, by breaking one of the molecule’s critical bonds. Penicillin can successfully wipe out all susceptible bacterial strains but leaves these resistant strains behind to continue colonizing and growing. Antibiotic resistance poses a serious problem; researchers are attempting to discover new antibiotics, but are in an arms race against bacteria with resistant mutations, and the pace of discovery has slowed considerably.

At the Broad Institute, researchers in the Chemical Biology Program and Platform have access to compounds that occur in nature (like penicillin) but are also riffing on nature’s design to synthesize small molecules. By creating a diverse library of compounds, they aim to help scientists discover new drugs that could help in the fight against pathogens and other human diseases.