One of the major advances of twentieth-century medicine is the discovery of penicillin. Penicillin is a member of the class of drugs known as antibiotics. These drugs either kill (bacteriocidal) or arrest the growth of (bacteriostatic) bacteria, fungi (yeast), as well as several other classes of infectious organisms. Antibiotics are ineffective against viruses. Prior to the advent of penicillin bacterial infections such as pneumonia and sepsis (blood poisoning--the infecting organism invades the bloodstream) were usually fatal. Once the use of penicillin became widespread, fatality rates from pneumonia dropped precipitously.
The discovery of penicillin marked the beginning of a new era in the fight against disease. Scientists had known since the mid-nineteenth century that bacteria were responsible for someinfectious diseases, but they were virtually helpless to stop them. Then, in 1928, Alexander Fleming (1881-1955), a Scottish bacteriologist working at St. Mary's Hospital in London, stumbled onto a powerful new weapon.
Fleming's research centered on the bacterium Staphylococcus, a class of bacteria that caused infections such as pneumonia, abscesses, post-operative wound infections, and sepsis. To study these bacteria he grew them in glass Petri dishes on a substance called agar, in his laboratory. In August, 1928 he noticed that some of the Petri dishes in which the bacteria were growing had become contaminated with mold, which he later identified as belonging to the Penicillium family.
Fleming noted that bacteria in the vicinity of the mold had died. Exploring further, Fleming found that the mold killed several,but not all, types of bacteria. He also found that an extract from the mold did not damage healthy tisssue in animals. However, growing the mold and collecting even tiny amounts of the active ingredient--penicillin--was extremely difficult. Fleming did, however, publish his results in the medical literature in 1928.
Ten years later, other researchers picked up where Fleming had left off. Working in Oxford, England, a team led by Howard Florey (1898-1968), an Australian, and Ernst Chain, a refugee from Nazi Germany, came across Fleming's study and confirmed his findings in their laboratory. They too had problems growing the mold and found it very difficult to isolate the active ingredient
Another researcher on their team, Norman Heatley, developed better production techniques, and the team was able to produce enough penicillin to conduct tests in humans. In 1941 the team announced that penicillin could combat disease in humans. Unfortunately, producing penicillin was still a very difficult process and supplies of the new drug were extremely limited. Working in the United States, Heatley and other scientists improved production and began making large quantities of the drug. Owing to this success, penicillin was avilable to treat wounded soldiers by the latter part of World War II. Fleming, Florey, and Chain were awarded the Noble Prize in medicine. Heatley received an honorary M.D. from Oxford University in 1990.
Penicillin's mode of action is blocking the construction of cell walls in certain bacteria. The bacteria must be reproducing for penicillin to work, thus there is always some lag time between dosage and response.
Bacteria are divided into gram-positive and gram-negative classes based on a laboratory test called the Gram-staining procedure. The Gram-staining procedure uses special dyes that cause Gram-negative bacteria to turn pink and gram-positive bacteria to become purplish black. Classifying bacteria as gram-negative or gram-positive aids in identifying the bacterial species.
The mechanism of action of penicillin at the molecular level is still not completely understood. It is known that the initial step is the binding of penicillin to penicillin-binding proteins (PBPs) which are located in the cell wall. Some PBPs are inhibitors of cell autolytic enzymes that literally eat the cell wall and are most likely necessary during cell division. Other PBPs are enzymes that are involved in the final step of cell wall synthesis called transpeptidation. These latter enzymes are outside the cell membrane and link cell wall components together by joining glycopeptide polymers together to form peptidoglycan. The bacterial cell wall owes its strength to layers composed of peptidoglycan (also known as murein or mucopeptide). Peptidoglycan is a complex polymer composed of alternating N-acetylglucosamine and N-acetylmuramic acid as a backbone off of which a set of identical tetrapeptide side chains branch from the N-acetylmuramic acids, and a set of identical peptide cross-bridges also branch. The tetrapeptide side chains and the cross-bridges vary from species to species, but the backbone is the same in all bacterial species.
Each peptidoglycan layer of the cell wall is actually a giant polymer molecule because all peptidoglycan chains are cross-linked. In gram-positive bacteria there may be as many as 40 sheets of peptidoglycan, making up to 50% of the cell wall material. In gram-negative bacteria, there are only one or two sheets (about 5-10% of the cell wall material). In general, penicillin G, that is, the penicillin that Fleming discovered, has high activity against gram-positive bacteria and low activity against gram-negative bacteria (with some exceptions).
Penicillin acts by inhibiting peptidoglycan synthesis by blocking the final transpeptidation step in the synthesis of peptidoglycan. It also removes the inactivator of the inhibitor of autolytic enzymes, and the autolytic enzymes then lyse the cell wall, and the bacterium ruptures. This latter is the final bacteriocidal event.
Since the 1940s, many other antibiotics have been developed. Some of these are based on the molecular structure of penicillin, but others are completely unrelated. At one time it was believed that science had conquered bacterial infections. However, in the late twentieth century, bacterial resistance to antibiotics--including penicillin--was recognized as a potential threat to this success. A classic example is the Staphylococcus bacterium, the very species Fleming had found killed by penicillin on his Petri dishes. In 1999 essentially all Staphylococcus bacteria are resistant to penicillin G. Continuing research so far has been able to keep pace with emerging resistant strains of bacteria. We must be judicious about our use of antibiotics, however, so that we continue to be able to combat bacterial disease.
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