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86 years ago on September 28th, penicillin was discovered by Alexander Fleming. The Scottish scientist quite serendipitously stumbled upon a mold growing in one of his contaminated Staphylococcus plate cultures. What he found was that no bacteria could colonize within a certain radius of the mold. After growing a pure culture of the Penicillium notatum mold, he began doing clinical trials to determine if it could last long enough in the body to kill bacteria. Penicillin saved many lives during World War II and Fleming received many honors (including a Nobel Prize) for his work. In 1945, Dorothy Crowfoot Hodgkin discovered the chemical structure of penicillin, and it began being mass produced. Unfortunately, many bacteria are resistant to penicillin due to misuse over the past five decades.

So how does penicillin work?

Bacteria constantly break down and rebuild their cell walls. Penicillins interfere with the enzyme that forms the peptidoglycan cross-links that make the cell wall strong. These antibiotics have a four-membered β-lactam ring which binds to the enzyme DD-transpeptidase as a substrate. This deactivates the enzyme so that the bacteria are continuing to break down their cell walls but cannot rebuild them. The continuous breaking down of the cell and the osmotic pressure cause the cell to lyse and die.

As you can probably tell, penicillins are most effective with gram-positive bacteria. This is because gram-negative bacteria have an outer membrane (lipid-based) surrounding their cell walls. Therefore, it is more difficult for the penicillins to access the cell wall enzymes.

Many bacteria have become resistant to penicillin by making β-lactamase, an enzyme that breaks the β-lactam ring of penicillins (rendering the antibiotic unable to bind to the transpeptidase enzyme). This can be countered by prescribing penicillin along with a β-lactamase inhibitor.

So Happy Birthday, Penicillin! Sorry for overusing you, but thanks for helping us out with syphilis!

Penicillin Simple Mechanism Happy Birthday Penicillin