History of Penicillin Development

Overview

This lecture traces the discovery, development, and mass production of penicillin, exploring how it became the first widely used antibiotic and transformed the pharmaceutical industry.

Early Research and Fleming’s Discovery

• Almroth Wright founded the Inoculation Department at St. Mary's Hospital, focusing on vaccines and antiseptics.
• Alexander Fleming joined Wright’s lab in 1906 and later investigated antimicrobial agents.
• Fleming discovered lysozyme in bodily fluids, which had mild antibacterial effects but limited clinical use.
• In 1928, Fleming accidentally discovered penicillin when a Penicillium mold killed staphylococci on a petri dish.
• Fleming named the substance penicillin and published his findings in 1929, but could not purify it or demonstrate strong clinical utility.

Penicillin’s Mechanism and Initial Challenges

• Penicillin is most effective against Gram-positive bacteria due to their thick peptidoglycan cell walls.
• It contains a beta-lactam ring, which blocks the enzyme transpeptidase, stopping bacterial cell wall synthesis.
• Fleming’s original findings were limited by low purity and production challenges, so penicillin research stalled.

Florey, Chain, and the Oxford Team

• Howard Florey and Ernst Chain at Oxford revisited penicillin research in the late 1930s.
• Norman Heatley improved mold cultivation and penicillin extraction techniques.
• Animal trials showed penicillin was effective and safe in treating bacterial infections.
• Early human trials were promising but limited by low supply of the drug.

Scaling Up Production and US Involvement

• UK drug companies could not scale up penicillin production during WWII; Florey and Heatley sought help in the US.
• Collaboration with USDA’s Peoria lab led to breakthroughs in fermentation and finding high-yield molds.
• Adding corn steep liquor to growth media and deep-tank fermentation greatly boosted yields.
• Mary Hunt found a cantaloupe with a mold that produced vastly more penicillin, becoming the primary source.

Penicillin and the Pharmaceutical Industry

• US government, via the OSRD, partnered with private drug companies for large-scale production.
• Companies like Merck, Pfizer, and Eli Lilly received government contracts and prioritized penicillin supply for the military.
• Government subsidies and contracts consolidated the industry, making penicillin production highly profitable post-war.
• By 1945, penicillin was widely available, changing infectious disease therapy and boosting the US pharmaceutical sector.

Limitations and Legacy of Penicillin

• Widespread allergies to penicillin were identified soon after its rollout.
• Bacteria quickly developed resistance; by the 1960s, most Staphylococcus aureus infections were penicillin-resistant.
• Penicillin was ineffective against Mycobacterium tuberculosis; additional antibiotics like streptomycin were needed.
• Penicillin’s success established the antibiotic era and transformed drug discovery and pharmaceutical manufacturing.

Key Terms & Definitions

• Antibiotic — a substance that kills or inhibits the growth of bacteria.
• Lysozyme — an enzyme in bodily fluids with mild antibacterial activity.
• Gram-positive bacteria — bacteria with a thick peptidoglycan cell wall, stained purple by Gram staining.
• Beta-lactam ring — a chemical structure in penicillin that inhibits bacterial cell wall synthesis.
• Transpeptidase — an enzyme essential for bacterial cell wall cross-linking.
• Deep-tank fermentation — industrial method for growing microorganisms in large, aerated tanks.
• Penicillin resistance — the ability of bacteria to survive despite penicillin treatment.
• OSRD (Office of Scientific Research and Development) — US government agency funding scientific research during WWII.

Action Items / Next Steps

• Review the mechanism of action for beta-lactam antibiotics.
• Prepare for next class discussion on antibiotic resistance and the discovery of streptomycin.
• Read about the rise of pharmaceutical manufacturing post-World War II.