Allergy to penicillin is an example of what type of hypersensitivity
Main article: Side effects of penicillin
Common (≥ 1% of people) adverse drug reactions associated with use of the penicillins include diarrhoea, hypersensitivity, nausea, rash, neurotoxicity, urticaria, and superinfection (including candidiasis). Infrequent adverse effects (–1% of people) include fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in people with epilepsy), and pseudomembranous colitis. Penicillin can also induce serum sickness or a serum sickness-like reaction in some individuals. Serum sickness is a type III hypersensitivity reaction that occurs one to three weeks after exposure to drugs including penicillin.
It is not a true drug allergy, because allergies are type I hypersensitivity reactions, but repeated exposure to the offending agent can result in an anaphylactic reaction.[medical citation needed] Allergy will happen in % of people, presenting as a skin rash after exposure. IgE-mediated anaphylaxis will happen in approximately % of patients.
Pain and inflammation at the injection site are also common for parenterally istered benzathine benzylpenicillin, benzylpenicillin, and, to a lesser extent, procaine benzylpenicillin.[medical citation needed]
Penicillin inhibits activity of enzymes that are needed for the cross linking of peptidoglycans in bacterial cell walls, which is the final step in cell wall biosynthesis.
It does this by binding to penicillin binding proteins with the beta-lactam ring, a structure found on penicillin molecules. This causes the cell wall to weaken due to fewer cross links and means water uncontrollably flows into the cell because it cannot maintain the correct osmotic gradient. This results in cell lysis and death.
Some bacteria produce enzymes that break below the beta-lactam ring, called beta-lactamases, which make the bacteria resistant to penicillin. Therefore, some penicillins are modified or given with other drugs for use against antibiotic resistant bacteria or in immunocompromised patients.
Use of clavulanic acid or tazobactam, beta-lactamase inhibitors, alongside penicillin gives penicillin activity against beta-lactamase producing bacteria. Beta lactamase inhibitors irreversibly bind to beta-lactamase preventing it from breaking below the beta-lactam rings on the antibiotic molecule. Alternatively, flucloxacillin is a modified penicillin that has activity against beta-lactamase producing bacteria due to an acyl side chain that protects the beta-lactam ring from beta-lactamase.
Mechanism of action
Main article: Beta-lactam antibiotic
Bacteria constantly remodel their peptidoglycan cell walls, simultaneously building and breaking below portions of the cell wall as they grow and divide.
β-Lactam antibiotics inhibit the formation of peptidoglycan cross-links in the bacterial cell wall; this is achieved through binding of the four-membered β-lactam ring of penicillin to the enzymeDD-transpeptidase. As a consequence, DD-transpeptidase cannot catalyze formation of these cross-links, and an imbalance between cell wall production and degradation develops, causing the cell to rapidly die.
The enzymes that hydrolyze the peptidoglycan cross-links continue to function, even while those that form such cross-links do not.
This weakens the cell wall of the bacterium, and osmotic pressure becomes increasingly uncompensated—eventually causing cell death (cytolysis). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and autolysins, which further digest the cell wall’s peptidoglycans. The little size of the penicillins increases their potency, by allowing them to penetrate the entire depth of the cell wall. This is in contrast to the glycopeptide antibioticsvancomycin and teicoplanin, which are both much larger than the penicillins.
Gram-positive bacteria are called protoplasts when they lose their cell walls.
Gram-negative bacteria do not lose their cell walls 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 their disruption of bacterial protein synthesis within the cell. This results in a lowered MBC for susceptible organisms.
Penicillins, love other β-lactam antibiotics, block not only the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosyntheticorganelles of the glaucophytes, and the division of chloroplasts of bryophytes.
In contrast, they own 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.
The chemical structure of penicillin is triggered with a extremely precise, pH-dependent directed mechanism, effected by a unique spatial assembly of molecular components, which can activate by protonation. It can travel through bodily fluids, targeting and inactivating enzymes responsible for cell-wall synthesis in gram-positive bacteria, meanwhile avoiding the surrounding non-targets.
Penicillin can protect itself from spontaneous hydrolysis in the body in its anionic form, while storing its potential as a strong acylating agent, activated only upon approach to the target transpeptidase enzyme and protonated in the athletic centre. This targeted protonation neutralizes the carboxylic acid moiety, which is weakening of the β-lactam ring N–C(=O) bond, resulting in a self-activation. Specific structural requirements are equated to constructing the perfect mouse trap for catching targeted prey.
Penicillin has low protein binding in plasma, the bioavailability of penicillin depends on the type; penicillin G has a low bioavailability, under 30%, whereas penicillin V has a higher bioavailability between 60 and 70%.
Penicillin has a short half life and is excreted via the kidneys.
The term «penam» is used to describe the common core skeleton of a member of the penicillins. This core has the molecular formula R-C9H11N2O4S, where R is the variable side chain that differentiates the penicillins from one another.
The penam core has a molar mass of g/mol, with larger penicillins having molar mass near —for example, cloxacillin has a molar mass of g/mol. The key structural feature of the penicillins is the four-membered β-lactam ring; this structural moiety is essential for penicillin’s antibacterial activity. The β-lactam ring is itself fused to a five-membered thiazolidine ring. The fusion of these two rings causes the β-lactam ring to be more reactive than monocyclic β-lactams because the two fused rings distort the β-lactam amide bond and therefore remove the resonance stabilisation normally found in these chemical bonds.
|Names||Method of istration||Notes|
|Penicillin G, benzylpenicillin||IV or IM||It has high urinary excretion and is produced as a salt of potassium or sodium.|
|Penicillin V, phenoxymethylpenicillin||By mouth||It is less athletic than benzylpenicillin against Gram-negative bacteria.|
|Benzathine benzylpenicillin, benzathine penicillin G||IM||Benzathine is a stabilizer that causes slower release over two to four weeks.|
|Procaine benzylpenicillin, penicillin G procaine||IM||Slow release.|
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 athletic growth. Production is also limited by feedback in the synthesis pathway of penicillin.
- α-ketoglutarate + AcCoA → homocitrate → L-α-aminoadipic acid → L-lysine + β-lactam
The by-product, l-lysine, inhibits the production of homocitrate, so the presence of exogenous lysine should be avoided in penicillin production.
The Penicillium cells are grown using a technique called fed-batch culture, in which the cells are constantly subject to stress, which is required for induction of penicillin production. The available carbon sources are also important: glucose inhibits penicillin production, whereas lactose does not. The pH and the levels of nitrogen, lysine, phosphate, and oxygen of the batches must also be carefully controlled.
The biotechnological method of directed evolution has been applied to produce by mutation a large number of Penicillium strains. These techniques include error-prone PCR, DNA shuffling, ITCHY, and strand-overlap PCR.
Semisynthetic penicillins are prepared starting from the penicillin nucleus 6-APA.
Overall, there are three main and significant steps to the biosynthesis of penicillin G (benzylpenicillin).
- The second step in the biosynthesis of penicillin G is the oxidative conversion of linear ACV into the bicyclic intermediate isopenicillin N by isopenicillin N synthase (IPNS), which is encoded by the gene pcbC. Isopenicillin N is a extremely feeble intermediate, because it does not show strong antibiotic activity.
- The first step is the condensation of three amino acids—L-α-aminoadipic acid, L-cysteine, L-valine into a tripeptide. Before condensing into the tripeptide, the amino acid L-valine must undergo epimerization to become D-valine. The condensed tripeptide is named δ-(L-α-aminoadipyl)-L-cysteine-D-valine (ACV).
The condensation reaction and epimerization are both catalyzed by the enzyme δ-(L-α-aminoadipyl)-L-cysteine-D-valine synthetase (ACVS), a nonribosomal peptide synthetase or NRPS.
- The final step is a transamidation by isopenicillin N N-acyltransferase, in which the α-aminoadipyl side-chain of isopenicillin N is removed and exchanged for a phenylacetyl side-chain. This reaction is encoded by the gene penDE, which is unique in the process of obtaining penicillins.
Main article: History of penicillin
Structure determination and entire synthesis
The chemical structure of penicillin was first proposed by Edward Abraham in  and was later confirmed in using X-ray crystallography by Dorothy Crowfoot Hodgkin, who was also working at Oxford. She later received the Nobel prize for this and other structure determinations.
Chemist John C. Sheehan at the Massachusetts Institute of Technology (MIT) completed the first chemical synthesis of penicillin in  Sheehan had started his studies into penicillin synthesis in , and during these investigations developed new methods for the synthesis of peptides, as well as new protecting groups—groups that mask the reactivity of certain functional groups. Although the initial synthesis developed by Sheehan was not appropriate for mass production of penicillins, one of the intermediate compounds in Sheehan’s synthesis was 6-aminopenicillanic acid (6-APA), the nucleus of penicillin.[pageneeded] Attaching diverse groups to the 6-APA ‘nucleus’ of penicillin allowed the creation of new forms of penicillin.
Starting in the tardy 19th century there had been numerous accounts by scientists and physicians on the antibacterial properties of the diverse types of moulds including the mould penicillium but they were unable to discern what process was causing the effect. The effects of penicillium mould were finally isolated in by Scottish scientist Alexander Fleming, in work that seems to own been independent of those earlier observations. Fleming recounted that the date of his discovery of penicillin was on the morning of Friday 28 September  The traditional version of this tale describes the discovery as a serendipitous accident: in his laboratory in the basement of StMary’s Hospital in London (now part of Imperial College), Fleming noticed a Petri dish containing Staphylococci that had been mistakenly left open was contaminated by blue-green mould from an open window, which formed a visible growth. There was a halo of inhibited bacterial growth around the mould.
Fleming concluded that the mould released a substance that repressed the growth and caused lysing of the bacteria.
Once Fleming made his discovery he grew a pure culture and discovered it was a Penicillium mould, now known as Penicillium chrysogenum. Fleming coined the term «penicillin» to describe the filtrate of a broth culture of the Penicillium mould. Fleming asked C. J. La Touche to assist identify the mould, which he incorrectly identified as Penicillium rubrum (later corrected by Charles Thom). He expressed initial optimism that penicillin would be a useful disinfectant, because of its high potency and minimal toxicity in comparison to antiseptics of the day, and noted its laboratory worth in the isolation of Bacillus influenzae (now called Haemophilus influenzae).
Fleming was a famously poor communicator and orator, which meant his findings were not initially given much attention. He was unable to convince a chemist to assist him extract and stabilize the antibacterial compound found in the broth filtrate.
Despite this, he remained interested in the potential use of penicillin and presented a paper entitled «A Medium for the Isolation of Pfeiffer’s Bacillus» to the Medical Research Club of London, which was met with little interest and even less enthusiasm by his peers.
Had Fleming been more successful at making other scientists interested in his work, penicillin for medicinal use would possibly own been developed years earlier.
Despite the lack of interest of his fellow scientists, he did conduct several experiments on the antibiotic substance he discovered. The most significant 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. The one test that modern scientists would discover missing from his work was the test of penicillin on an infected animal, the results of which would likely own sparked grand interest in penicillin and sped its development by almost a decade. 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, 
By tardy , the Oxford team under Howard Florey had devised a method of mass-producing the drug, but yields remained low. In , Florey and Heatley travelled to the US in order to interest pharmaceutical companies in producing the drug and inform them about their process.
Florey and Chain shared the Nobel Prize in Medicine with Fleming for their work.
The challenge of mass-producing this drug was daunting. On March 14, , the first patient was treated for streptococcal sepsis with US-made penicillin produced by Merck & Co. Half of the entire supply produced at the time was used on that one patient, Anne Miller. By June , just enough US penicillin was available to treat ten patients. In July , the War Production Board drew up a plan for the mass distribution of penicillin stocks to Allied troops fighting in Europe. The results of fermentation research on corn steep liquor at the Northern Regional Research Laboratory at Peoria, Illinois, allowed the United States to produce million doses in time for the invasion of Normandy in the spring of After a worldwide search in , a mouldy cantaloupe in a Peoria, Illinois market was found to contain the best strain of mould for production using the corn steep liquor process.Pfizer scientist Jasper H.
Kane suggested using a deep-tank fermentation method for producing large quantities of pharmaceutical-grade penicillin. Large-scale production resulted from the development of a deep-tank fermentation plant by chemical engineerMargaret Hutchinson Rousseau. As a direct result of the war and the War Production Board, by June , over billion units per year were being produced.
G. Raymond Rettew made a significant contribution to the American war effort by his techniques to produce commercial quantities of penicillin, wherein he combined his knowledge of mushroom spawn with the function of the Sharples Cream Separator. By , Rettew’s lab was producing most of the world’s 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. Methods for mass production of penicillin were patented by Andrew Jackson Moyer in  Florey had not patented penicillin, having been advised by Sir Henry Dale that doing so would be unethical.
Penicillin is actively excreted, and about 80% of a penicillin dose is cleared from the body within three to four hours of istration.
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 discover 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 istered 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. Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.[needs update]
After World War II, Australia was the first country to make the drug available for civilian use.
In the U.S., penicillin was made available to the general public on March 15, 
In , Cecil George Paine, a pathologist at the Royal Infirmary in Sheffield, attempted to use 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, He then cured four additional patients (one adult and three infants) of eye infections, and failed to cure a fifth.
In , Australian scientist Howard Florey (later Baron Florey) and a team of researchers (Ernst Boris Chain, Edward Abraham, Arthur Duncan Gardner, Norman Heatley, Margaret Jennings, J.
Orr-Ewing and G. Sanders) at the Sir William Dunn School of Pathology, University of Oxford made progress in showing the in vivo bactericidal action of penicillin. In , they showed that penicillin effectively cured bacterial infection in mice. In , they treated a policeman, Albert Alexander, with a severe face infection; his condition improved, but then supplies of penicillin ran out and he died.
Subsequently, several other patients were treated successfully. In December , survivors of the Cocoanut Grove fire in Boston were the first burn patients to be successfully treated with penicillin.
Developments from penicillin
The narrow range of treatable diseases or «spectrum of activity» of the penicillins, along with the poor activity of the orally athletic phenoxymethylpenicillin, led to the search for derivatives of penicillin that could treat a wider range of infections. The isolation of 6-APA, the nucleus of penicillin, allowed for the preparation of semisynthetic penicillins, with various improvements over benzylpenicillin (bioavailability, spectrum, stability, tolerance).
The first major development was ampicillin in It offered a broader spectrum of activity than either of the original penicillins. Further development yielded β-lactamase-resistant penicillins, including flucloxacillin, dicloxacillin, and methicillin. These were significant for their activity against β-lactamase-producing bacterial species, but were ineffective against the methicillin-resistant Staphylococcus aureus (MRSA) strains that subsequently emerged.
Another development of the line of true penicillins was the antipseudomonal penicillins, such as carbenicillin, ticarcillin, and piperacillin, useful for their activity against Gram-negative bacteria.
However, the usefulness of the β-lactam ring was such that related antibiotics, including the mecillinams, the carbapenems and, most significant, the cephalosporins, still retain it at the middle of their structures.
The term «penicillin» was used originally for benzylpenicillin, penicillin G. Currently, «Penicillin» is used as a generic term for antibiotics that contain the beta lactam unit in the chemical structure.
For example, amoxicillin tablets may be labelled as «a penicillin». Other derivatives such as procaine benzylpenicillin (procaine penicillin), benzathine benzylpenicillin (benzathine penicillin), and phenoxymethylpenicillin (penicillin V) are also described as «penicillins». Procaine penicillin and benzathine penicillin own the same antibacterial activity as benzylpenicillin but act for a longer period of time. Phenoxymethylpenicillin is less athletic against gram-negative bacteria than benzylpenicillin. 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.
While the number of penicillin-resistant bacteria is increasing, penicillin can still be used to treat a wide range of infections caused by certain susceptible bacteria, including those in the Streptococcus, Staphylococcus, Clostridium, Neisseria, and Listeria genera.
The following list illustrates minimum inhibitory concentration susceptibility data for a few medically significant bacteria:
- Neisseria meningitidis: from less than or equal to μg/ml to μg/ml
- Listeria monocytogenes: from less than or equal to μg/ml to μg/ml
- Staphylococcus aureus: from less than or equal to μg/ml to more than 32 μg/ml