Penicillin (sometimes abbreviated PCN or pen) is a group of antibiotics derived from ''Penicillium'' fungi.

Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases such as syphilisand Staphylococcus infections. Penicillins are still widely used today, though many types of bacteria are now resistant. All penicillins are Beta-lactam antibiotics and are used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. The term "penicillin" can also refer to the ''mixture'' of substances that are naturally, and organically, produced. The term "penam" is used to describe the core skeleton of a member of a penicillin antibiotic. This skeleton has the molecular formula R-C 9H11N2O4S, where R is a variable side chain. Normal penicillin has a molecular weight of 313 to 334 g/mol (latter for penicillin G). Penicillin types with additional molecular groups attached may have a molar mass around 500 g/mol. For example, cloxacillin has a molar mass of 476 g/mol and dicloxacillin has a molar mass of 492 g/mol.

Penicillin Mechanism

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-Lactam antibiotics work by inhibiting the formation of peptidoglycan crosslinks in the bacterial cell wall. The -lactam moiety (functional group) of penicillin binds to the enzyme (DD-transpeptidase) that links the peptidoglycan molecules in bacteria, which weakens the cell wall of the bacterium (in other words, the antibiotic causes cytolysis or death due to osmotic pressure). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and autolysins, which further digest the bacteria's existing peptidoglycan. Gram-positive bacteria are called protoplasts when they lose their cell wall. Gram-negative bacteria do not lose their cell wall completely and are called spheroplasts after treatment with penicillin. Penicillin shows a synergistic effect with aminoglycosides, since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing its disruption of bacterial protein synthesis within the cell. This results in a lowered MBC for susceptible organisms.

Penicillins, like other -lactam antibiotics, block not only the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosynthetic organelles of the glaucophytes, and the division of chloroplasts of bryophytes. In contrast, they have no effect on the plastids of the highly developed vascular plants. This supports the endosymbiotic theory of the evolution of plastid division in land plants.

Penicillin Biosynthesis

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Overall, there is a total of three main and important steps to the biosynthesis ofpenicillin G (benzylpenicillin)

The first step in the biosynthesis of penicillin G is the condensation of three amino acids L--aminoadipic acid, L-cysteine, L-valine into a tripeptide. Before condensing into a tripeptide, the amino acid L-valine will undergo epimerization and become D-valine. After the condensation, the tripeptide is named -(L--aminoadipyl)-L-cysteine-D-valine, which is also known as ACV. While this reaction occurs, we must add in a required catalytic enzyme ACVS, which is also known as -(L-aminoadipyl)-L-cysteine-D-valine synthetase. This catalytic enzyme ACVs is required for the activation of the three amino acids before condensation and the epimerization of transforming L-valine to D-valine. The second step in the biosynthesis of penicillin G is to use an enzyme to change ACV into isopenicillin N. The enzyme is isopenicillin N synthase with the gene pcbC enclosed. The tripeptide on the ACV will then undergo oxidation, which then allows a ring closure so that a bicyclic ring is formed. He showed that, if ''Penicillium notatum'' was grown in the appropriate substrate, it would exude a substance with antibiotic properties, which he dubbed penicillin. This serendipitous observation began the modern era of antibiotic discovery. The development of penicillin for use as a medicine is attributed to the Australian Nobel laureate Howard Walter Florey together with the German Nobel laureate Ernst Chain and the English biochemist Norman Heatley.

However, several others reported the bacteriostatic effects of ''Penicillium'' earlier than Fleming. The use of bread with a blue mould (presumably penicillium) as a means of treating suppurating wounds was a staple of folk medicine in Europe since the Middle Ages. The first published reference appears in the publication of the Royal Society in 1875, by John Tyndall. Ernest Duchesne documented it in an 1897 paper, which was not accepted by the Institut Pasteur because of his youth. In March 2000, doctors at the San Juan de Dios Hospital in San Jos, Costa Rica published the manuscripts of

the Costa Rican scientist and medical doctor Clodomiro (Clorito) Picado Twight (18871944). They reported Picado's observations on the inhibitory actions of fungi of the genus ''Penicillium'' between 1915 and 1927. Picado reported his discovery to the Paris Academy of Sciences, yet did not patent it, even though his investigations started years before Fleming's. Joseph Lister was experimenting with penicillum in 1871 for his Aseptic surgery. He found that it weakened the microbes but then he dismissed the fungi. Fleming recounted that the date of his breakthrough was on the morning of Friday, September 28, 1928. It was a fortuitous accident: in his laboratory in the basement of St. Mary's Hospital in London (now part of Imperial College), Fleming noticed a petri dish containing ''Staphylococcus'' plate culture he had mistakenly left open, which was contaminated by blue-green mould, which had formed a visible growth. There was a halo of inhibited bacterial growth around the mould. Fleming concluded that the mould was releasing a substance that was repressing the growth and lysing the bacteria. He grew a pure culture and discovered that it was a ''Penicillium'' mould, now known to be ''Penicillium notatum''. Charles Thom, an American specialist working at the U.S. Department of Agriculture, was the acknowledged expert, and Fleming referred the matter to him. Fleming coined the term "penicillin" to describe the filtrate of a broth culture of the ''Penicillium'' mould. Even in these early stages, penicillin was found to be most effective against Grampositive bacteria, and ineffective against Gram-negative organisms and fungi. He expressed initial optimism that penicillin would be a useful disinfectant, being highly potent with minimal toxicity compared to antiseptics of the day, and noted its laboratory value in the isolation of "''Bacillus influenzae''" (now ''Haemophilus influenzae''). After further experiments, Fleming was convinced that penicillin could not last long enough in the human body to kill pathogenic bacteria, and stopped studying it after 1931. He restarted clinical trials in 1934, and continued to try to get someone to purify it until 1940.

Medical application
In 1930, Cecil George Paine, a pathologist at the Royal Infirmary in Sheffield, attempted to use penicillin to treat sycosis barbaeeruptions in beard follicles, but was unsuccessful, probably because the drug did not penetrate the skin deeply enough. Moving on to ophthalmia neonatorum; a gonococcal infection in infants, he achieved the first recorded cure with penicillin, on November 25, 1930. He then cured four additional patients (one adult and three infants) of eye infections, failing to cure a fifth. In 1939, Australian scientist Howard Florey (later Baron Florey) and a team of researchers (Ernst Boris Chain, A. D. Gardner, Norman Heatley, M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn School of Pathology, University of Oxford made significant progress in showing the ''in vivo'' bactericidal action of penicillin. Their attempts to treat humans failed due to insufficient volumes of penicillin (the first patient treated was Reserve

Constable Albert Alexander), but they proved it harmless and effective on mice. Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary in Oxford, England. These trials continue to be cited by some sources as the first cures using penicillin, though the Paine trials took place earlier.

Mass production
The chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin in 1945. Penicillin has since become the most widely used antibiotic to date, and is still used for many Gram-positive bacterial infections. A team of Oxford research scientists led by Australian Howard Florey and including Ernst Boris Chain and Norman Heatley devised a method of mass-producing the drug. Florey and Chain shared the 1945 Nobel prize in medicine with Fleming for their work. After World War II, Australia was the first country to make the drug available for civilian use. Chemist John C. Sheehan at MIT completed the first total synthesis of penicillin and some of its analogs in the early 1950s, but his methods were not efficient for mass production. The challenge of mass-producing this drug was daunting. On March 14, 1942, the first patient was treated for streptococcal septicemia with U.S.-made penicillin produced by Merck & Co. Half of the total supply produced at the time was used on that one patient. By June 1942, there was just enough U.S. penicillin available to treat ten patients. A moldy cantaloupe in a Peoria, Illinois market in 1943 was found to contain the best and highestquality penicillin after a worldwide search. The discovery of the cantaloupe, and the results of fermentation research on corn steep liquor at the Northern Regional Research Laboratory at Peoria, Illinois, allowed the United States to produce 2.3 million doses in time for the invasion of Normandy in the spring of 1944. Large-scale production resulted from the development of deep-tank fermentation by chemical engineer Margaret Hutchinson Rousseau. G. Raymond Rettew made a significant contribution to the American war effort by his techniques to produce commercial quantities of penicillin. During World War II, penicillin made a major difference in the number of deaths and amputations caused by infected wounds among Allied forces, saving an estimated 12%15% of lives. Availability was severely limited, however, by the difficulty of manufacturing large quantities of penicillin and by the rapid renal clearance of the drug, necessitating frequent dosing. Penicillin is actively excreted, and about 80% of apenicillin dose is cleared from the body within three to four hours of administration. Indeed, during the early penicillin era, the drug was so scarce and so highly valued that it became common to collect the urine from patients being treated, so that the penicillin in the urine could be isolated and reused.

This was not a satisfactory solution, so researchers looked for a way to slow penicillin excretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for excretion, such that the transporter would preferentially excrete the competing molecule and the penicillin would be retained. The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are administered together, probenecid competitively inhibits the excretion of penicillin, increasing penicillin's concentration and prolonging its activity. Eventually, the advent of mass-production techniques and semi-synthetic penicillins resolved the supply issues, so this use of probenecid declined.