Instruct: Given a question, retrieve documents that can help answer the question.
Query: When was penicillin discovered?
Penicillin was discovered in 1928 by Scottish scientist Alexander Fleming.[3] People began using it to treat infections in 1942.[4] There are several enhanced penicillin families which are effective against additional bacteria; these include the antistaphylococcal penicillins, aminopenicillins and the antipseudomonal penicillins. They are derived from Penicillium fungi.[5]
The term "penicillin" is often used generically to refer to benzylpenicillin (penicillin G, the original penicillin found in 1928), procaine benzylpenicillin (procaine penicillin), benzathine benzylpenicillin (benzathine penicillin), and phenoxymethylpenicillin (penicillin V). Procaine penicillin and benzathine penicillin have the same antibacterial activity as benzylpenicillin but act for a longer period of time. Phenoxymethylpenicillin is less active against gram-negative bacteria than benzylpenicillin.[6][7] Benzylpenicillin, procaine penicillin and benzathine penicillin can only be given by intravenous or intramuscular injections, but phenoxymethylpenicillin can be given by mouth because of its acidic stability.[8]
During World War II, Bushnell Hospital treated approximately 13,000 military patients with various illnesses and injuries, and in 1944, it housed 3,286 GI–patients. The U.S. Army designated Bushnell Hospital as the military’s first center for the study of penicillin’s possible use. On April 1, 1943, the first shipment of penicillin arrived at Bushnell, and during the War, it administered penicillin more than any other institution in the United States. In addition to administering some of the first doses of penicillin, Ingram promoted its use to the surrounding Brigham community. In speech by then-Captain Alvin Ingram to the Rotary Club of Brigham City, he explained how penicillin was discovered in 1928 by Alexander Fleming, and extolled recent successes of administering the drug at nearby Bushnell Hospital. According to historian Richard Polenberg, “[w]artime advances in medicine, particularly in the production of penicillin (which first became generally available for civilian use in the spring of 1944) saved countless [military and civilian] lives.
Ernst Chain, Howard Florey and Edward Abraham succeeded in purifying the first penicillin, penicillin G, in 1942, but it did not become widely available outside the Allied military before 1945. Later, Norman Heatley developed the back extraction technique for efficiently purifying penicillin in bulk. The chemical structure of penicillin was first proposed by Abraham in 1942 and then later confirmed by Dorothy Crowfoot Hodgkin in 1945. Purified penicillin displayed potent antibacterial activity against a wide range of bacteria and had low toxicity in humans. Furthermore, its activity was not inhibited by biological constituents such as pus, unlike the synthetic sulfonamides. (see below) The development of penicillin led to renewed interest in the search for antibiotic compounds with similar efficacy and safety. For their successful development of penicillin, which Fleming had accidentally discovered but could not develop himself, as a therapeutic drug, Chain and Florey shared the 1945 Nobel Prize in Medicine with Fleming.
Cefalexin is a useful alternative to penicillins in patients with penicillin intolerance. For example, penicillin is the treatment of choice for respiratory tract infections caused by "Streptococcus", but cefalexin may be used as an alternative in penicillin-intolerant patients. Caution must be exercised when administering cephalosporin antibiotics to penicillin-sensitive patients, because cross sensitivity with beta-lactam antibiotics has been documented in up to 10% of patients with a documented penicillin allergy.
Penicillin is actively excreted, and about 80% of a penicillin 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.[48] 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.[48] Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.[11]
Alexander Fleming had first discovered penicillin by accident in 1928, but at that time believed it had little application. When Florey and his team recognised the potential of the discovery for combating bacterial infection, they faced the problem of how to manufacture penicillin in sufficient quantities to be of use. Heatley, although the junior member of the team, possessed a natural gift for ingenuity and invention. It was he who suggested transferring the active ingredient of penicillin back into water by changing its acidity, thus purifying the penicillin.
An example of semi-synthetic production involves the drug ampicillin. A beta lactam antibiotic just like penicillin, ampicillin was developed by adding an addition amino group (NH) to the R group of penicillin. This additional amino group gives ampicillin a broader spectrum of use than penicillin. Methicillin is another derivative of penicillin and was discovered in the late 1950s, the key difference between penicillin and methicillin being the addition of two methoxy groups to the phenyl group. These methoxy groups allow methicillin to be used against penicillinase producing bacteria that would otherwise be resistant to penicillin.
Penicillin was the first of the antibiotics to be discovered. After the discovery there was the issue of taking the raw naturally produced penicillin and developing a method so that wide-scale production of a clinically significant antibiotic could occur. Over the course of many years a team led by Florey and Chain and based in Oxford was able to successfully purify, concentrate, and produce the antibiotic.
The reaction was discovered in 1907 by the German chemist Hermann Staudinger. The reaction did not attract interest until the 1940s, when the structure of penicillin was elucidated. The "β"-lactam moiety of the first synthetic penicillin was constructed using this cycloaddition, and it remains a valuable tool in synthetic organic chemistry.
In 1959, Brockham Park became famous when Beecham scientists there discovered the penicillin nucleus, 6-APA (6-aminopenicillanic acid); This discovery allowed Beecham, working in tandem with Bristol-Myers, to synthesize of a number of new semisynthetic penicillins. Beecham marketed Broxil (phenethicillin), followed shortly by the more potent Celbenin (methicillin), which was active against "Staphylococcus aureus". The group continued to focus on pharmaceutical development, producing further semi-synthetic penicillins. However, when Penbritin (ampicillin) came on the market in 1961, Beecham's facilities were soon inadequate for the worldwide demand the drug generated. A complex at Worthing came on line in the early 1960s to produce phenethicillin, followed by the ability to produce 6-APA, the base for semisynthetic penicillins.
Fleming was modest about his part in the development of penicillin, describing his fame as the "Fleming Myth" and he praised Florey and Chain for transforming the laboratory curiosity into a practical drug. Fleming was the first to discover the properties of the active substance, giving him the privilege of naming it: penicillin. He also kept, grew, and distributed the original mould for twelve years, and continued until 1940 to try to get help from any chemist who had enough skill to make penicillin. But Sir Henry Harris said in 1998: "Without Fleming, no Chain; without Chain, no Florey; without Florey, no Heatley; without Heatley, no penicillin."
Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discovered. All β-lactam antibiotics (except for tabtoxinine-β-lactam, which inhibits glutamine synthetase) bind to PBPs, which are essential for bacterial cell wall synthesis. PBPs are members of a subgroup of enzymes called transpeptidases. Specifically, PBPs are DD-transpeptidases.
Penicillin G Penicillin K Penicillin N Penicillin O Penicillin V
Fleming also discovered very early that bacteria developed antibiotic resistance whenever too little penicillin was used or when it was used for too short a period. Almroth Wright had predicted antibiotic resistance even before it was noticed during experiments. Fleming cautioned about the use of penicillin in his many speeches around the world. On 26 June 1945, he made the following cautionary statements: "the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out ... In such cases the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted." He cautioned not to use penicillin unless there was a properly diagnosed reason for it to be used, and that if it were used, never to use too little, or for too short a period, since these are the circumstances under which bacterial resistance to antibiotics develops.
For decades biologists had been at work on the medicine that became penicillin. In 1928, Scottish biologist Alexander Fleming discovered a substance that killed a number of disease-causing bacteria. In 1929, he named the new substance "penicillin". His publications were largely ignored at first, but it became a significant antibiotic in the 1930s. In 1930, Cecil George Paine, a pathologist at Sheffield Royal Infirmary, used penicillin to treat sycosis barbae, eruptions in beard follicles, but was unsuccessful. 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, but failed to cure a fifth.
Penicillin is a secondary metabolite of certain species of Penicillium and is produced when growth of the fungus is inhibited by stress. It is not produced during active growth. Production is also limited by feedback in the synthesis pathway of penicillin.
At the time, it was known that the molecular weight of penicillin was around 350 g/mol, which was within the range of molecules that had already been chemically synthesized. The problem was the making the chemically unstable beta-lactam ring that was crucial to the antibiotic properties of the molecule. Beta-lactam antibiotics inhibit the formation of the peptidoglycan layer of the cell walls of Gram-positive bacteria. Most of the scientists experienced failure after failure because "the appropriate techniques and reactions for putting together the penicillin molecule simply had not yet been discovered." In the words of Sheehan, using traditional methods at the time was like "placing an anvil on top of a house of cards." After nine years of dogged work in the M.I.T. laboratories, this persistent organic chemist finally solved one of chemistry's most baffling problems at the time. In 1957, John C. Sheehan announced that his group had completed the first synthesis of penicillin V (one of the two most useful forms of the antibiotic). During the process, he had also produced an intermediate, 6-aminopenicillanic acid, which was later used as a foundation for preparing a variety of penicillins. This allowed researchers to combat the resistance that certain bacteria had developed to particular forms of the drug. Sheehan later published his involvement in the synthesis of penicillins in "The Enchanted Ring: The Untold Story of Penicillin", which noted a complex legal skirmish over his patents on penicillin synthesis involving M.I.T. and Beecham, a British industrial research laboratory that was also working on penicillins.
Recognition of antibiotic tolerance dates back to 1944 when Joseph Bigger, an Irish physician working in England, was experimenting with the recently discovered penicillin. Bigger used penicillin to lyse a suspension of bacteria and then inoculated culture medium with the penicillin-treated liquid. Colonies of bacteria were able to grow after antibiotic killing. The important observation that Bigger made was that this new population could again be killed by penicillin except for a small residual population. Hence the residual organisms were not antibiotic resistant mutants but rather a subpopulation of what he called ‘persisters’. The formation of persisters is now known to be a common phenomenon that can occur by the formation of persister cells prior to the antibiotic treatment or in response to a variety of antibiotics.
Despite the lack of interest of his fellow scientists, he did conduct several experiments on the antibiotic substance he discovered. The most important result proved it was nontoxic in humans by first performing toxicity tests in animals and then on humans. His subsequent experiments on penicillin's response to heat and pH allowed Fleming to increase the stability of the compound.[26] The one test that modern scientists would find missing from his work was the test of penicillin on an infected animal, the results of which would likely have sparked great interest in penicillin and sped its development by almost a decade.[24] The importance of his work has been recognized by the placement of an International Historic Chemical Landmark at the Alexander Fleming Laboratory Museum in London on November 19, 1999.[27]
A significant number of anti-infectives are based on natural products. The first antibiotic to be discovered, penicillin, was isolated from the mold "Penicillium". Penicillin and related beta lactams work by inhibiting DD-transpeptidase enzyme that is required by bacteria to cross link peptidoglycan to form the cell wall.
Common adverse drug reactions (≥ 1% of people) associated with use of the penicillins include diarrhoea, hypersensitivity, nausea, rash, neurotoxicity, urticaria, and superinfection (including candidiasis). Infrequent adverse effects (0.1–1% of people) include fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in people with epilepsy), and pseudomembranous colitis.
When penicillin is used at high doses hypokalemia, metabolic acidosis, and hyperkalemia can occur. Developing hypernatremia after administering high doses of penicillin can be a serious side effect.
In 1939, he joined Howard Florey to investigate natural antibacterial agents produced by microorganisms. This led him and Florey to revisit the work of Alexander Fleming, who had described penicillin nine years earlier. Chain and Florey went on to discover penicillin's therapeutic action and its chemical composition. Chain and Florey discovered how to isolate and concentrate the germ-killing agent in penicillin. Along with Edward Abraham he was also involved in theorising the beta-lactam structure of penicillin in 1942, which was confirmed by X-ray crystallography done by Dorothy Hodgkin in 1945. For this research, Chain, Florey, and Fleming received the Nobel Prize in 1945.
Félix d'Herelle (1873–1949) was a mainly self-taught French-Canadian microbiologist. In 1917 he discovered that "an invisible antagonist", when added to bacteria on agar, would produce areas of dead bacteria. The antagonist, now known to be a bacteriophage could pass through a Chamberland filter. He accurately diluted a suspension of these viruses and discovered that the highest dilutions (lowest virus concentrations), rather than killing all the bacteria, formed discrete areas of dead organisms. Counting these areas and multiplying by the dilution factor allowed him to calculate the number of viruses in the original suspension. He realised that he had discovered a new form of virus and later coined the term "bacteriophage".
Between 1918 and 1921 d'Herelle discovered different types of bacteriophages that could infect several other species of bacteria including "Vibrio cholerae". Bacteriophages were heralded as a potential treatment for diseases such as typhoid and cholera, but their promise was forgotten with the development of penicillin. Since the early 1970s, bacteria have continued to develop resistance to antibiotics such as penicillin, and this has led to a renewed interest in the use of bacteriophages to treat serious infections.
From 1945, Beecham Research Laboratories Ltd (which merged with SmithKline, then with Glaxo, to become GlaxoSmithKline) operated from Brockham Park at the southern end of the village.
In 1959, Brockham Park became famous when Beecham scientists there discovered the penicillin nucleus, 6-APA (6-aminopenicillanic acid); this discovery allowed the synthesis of a number of new semisynthetic penicillins. 
In 1959, Beecham marketed pheneticillin, followed shortly by methicillin (or meticillin), which is active against the bacterium "Staphylococcus aureus" ('golden staph'). In time some bacterial strains developed resistance to these antibiotics, such as the MRSA (for methicillin-resistant "Staphylococcus aureus"). The site is now a housing estate.