Penicillin

Penicillin (PCN or pen) is a group of antibiotics, derived originally from common moulds known as Penicillium moulds; which includes penicillin G (intravenous use), penicillin V (use by mouth), procaine penicillin, and benzathine penicillin (intramuscular use). Penicillin antibiotics were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci. They are still widely used today, though many types of bacteria have developed resistance following extensive use.

For the Japanese band, see Penicillin (band).

Penicillin
Penicillin core structure, where "R" is the variable group
Clinical data
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy
category
  • US: B (No risk in non-human studies) [1]
    Routes of
    administration    		Intravenous, intramuscular, by mouth
    Legal status
    Legal status
    • In general: ℞ (Prescription only)
    Pharmacokinetic data
    MetabolismLiver
    Elimination half-lifeBetween 0.5 and 56 hours
    ExcretionKidneys

    About 10% of people report that they are allergic to penicillin; however, up to 90% of this group may not actually be allergic.[2] Serious allergies only occur in about 0.03%.[2] Those who are allergic to penicillin are most often given cephalosporin C because of its functional groups.[3] All penicillins are β-lactam antibiotics, which are some of the most powerful and successful achievements in modern science.[3]

    Penicillin was discovered in 1928 by Scottish scientist Alexander Fleming.[4] People began using it to treat infections in 1942.[5] 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.[6] Fleming shared the 1945 Nobel Prize in Physiology or Medicine for his discovery, along with Oxford University scientists Howard Florey and Ernst Boris Chain (who developed improved ways to produce and concentrate the drug and prove its antibacterial effects).

    Medical uses

    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 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.[7][8] 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.[9]

    Susceptibility

    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:[10][11]

    • Listeria monocytogenes: from less than or equal to 0.06 μg/ml to 0.25 μg/ml
    • Neisseria meningitidis: from less than or equal to 0.03 μg/ml to 0.5 μg/ml
    • Staphylococcus aureus: from less than or equal to 0.015 μg/ml to more than 32 μg/ml

    Side effects
    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 (0.1–1% of people) include fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in people with epilepsy), and pseudomembranous colitis.[12] 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. Allergy will occur in 1-10% of people, presenting as a skin rash after exposure. IgE-mediated anaphylaxis will occur in approximately 0.01% of patients.[13][12]

    Pain and inflammation at the injection site are also common for parenterally administered benzathine benzylpenicillin, benzylpenicillin, and, to a lesser extent, procaine benzylpenicillin.

    Members
    NamesMethod of administrationNotes
    Penicillin G, benzylpenicillinIV or IMIt has high urinary excretion and is produced as a salt of potassium or sodium.
    Penicillin V, phenoxymethylpenicillinBy mouthIt is less active than benzylpenicillin against Gram-negative bacteria.
    Benzathine benzylpenicillin, benzathine penicillin GIMBenzathine is a stabilizer that causes slower release over two to four weeks.
    Procaine benzylpenicillin, penicillin G procaineIMSlow release.

    Natural penicillins
    • Penicillin G
    • Penicillin K
    • Penicillin N
    • Penicillin O
    • Penicillin V

    β-lactamase-resistant

    Aminopenicillins

    Carboxypenicillins

    Ureidopenicillins

    β-lactamase inhibitors

    Pharmacology

    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.[14][15] 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 down 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 down 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.[13]

    Mechanism of action
    Bacteria that attempt to grow and divide in the presence of penicillin fail to do so, and instead end up shedding their cell walls.[16]
    Penicillin and other β-lactam antibiotics act by inhibiting penicillin-binding proteins, which normally catalyze cross-linking of bacterial cell walls.

    Bacteria constantly remodel their peptidoglycan cell walls, simultaneously building and breaking down 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 enzyme DD-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.[17]

    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 small 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 antibiotics vancomycin and teicoplanin, which are both much larger than the penicillins.[18]

    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.[16]

    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.[19]

    Penicillins, like other β-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.[20]

    The chemical structure of penicillin is triggered with a very 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 active 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.[21]

    Pharmacokinetics

    Penicillin has low protein binding in plasma, the bioavailability of penicillin depends on the type; penicillin G has a low bioavailability, below 30%, whereas penicillin V has a higher bioavailability between 60 and 70%. Penicillin has a short half life and is excreted via the kidneys.[22]

    Structure
    Chemical structure of Penicillin G. The sulfur and nitrogen of the five-membered thiazolidine ring are shown in yellow and blue respectively. The image shows that the thiazolidine ring and fused four-membered β-lactam are not in the same plane.

    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 243 g/mol, with larger penicillins having molar mass near 450—for example, cloxacillin has a molar mass of 436 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.[23]

    History
    Main article: History of penicillin

    Discovery
    Alexander Fleming, who is credited with discovering penicillin in 1928.
    Sample of penicillium mould presented by Alexander Fleming to Douglas Macleod, 1935

    Starting in the late 19th century there had been accounts on the antibacterial properties of the mould Penicillium but they were unable to discern what process was causing the effect.[24] Scottish physician Alexander Fleming at St Mary's Hospital in London (now part of Imperial College) was the first to show that Penicillium rubrum (now reclassified as Penicillium rubens) had antibacterial property in 1928.[25] It was after a fungal contamination of his bacterial (Staphylococcus aureus) culture which he observed on 3 September 1928. He confirmed it with a new experiment on 28 September 1928.[26] He published his experiment in 1929 and called the antibacterial substance (the fungal extract) as penicillin.[27]

    C. J. La Touche identified the fungus as Penicillium rubrum (later reclassified by Charles Thom as P. notatum and P. chrysogenum, but later corrected as P. rubens).[28] Fleming expressed initial optimism that penicillin would be a useful antiseptic, because of its high potency and minimal toxicity in comparison to other antiseptics of the day, and noted its laboratory value in the isolation of Bacillus influenzae (now called Haemophilus influenzae).[29][30]

    Fleming did not convince anyone that his discovery was important.[29] This was largely because penicillin was difficult to isolate so that drug development was unthinkable. It is speculated that had Fleming been more successful at making other scientists interested in his work, penicillin would possibly have been developed years earlier.[29]

    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.[31]

    Medical application
    Florey (pictured), Fleming and Chain shared a Nobel Prize in 1945 for their work on penicillin.

    In 1930, Cecil George Paine, a pathologist at the Royal Infirmary in Sheffield, successfully treated ophthalmia neonatorum, a gonococcal infection in infants, with penicillin (fungal extract) on November 25, 1930.[32][33][34]

    In 1940, 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 making concentrated penicillin from fungal culture broth that showed both in vitro and in vivo bactericidal action.[35][36] In 1941, 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.[37] In December 1942, survivors of the Cocoanut Grove fire in Boston were the first burn patients to be successfully treated with penicillin.[38]

    Mass production
    A technician preparing penicillin in 1943

    As the medical application was established, the Oxford team found that it was impossible to produce usable amount from their labaratory.[37] In 1941, Florey and Heatley travelled to the US in order to interest pharmaceutical companies in producing the drug and inform them about their process.[37]

    Florey and Chain shared the 1945 Nobel Prize in Physiology or Medicine with Fleming for their work.

    On March 14, 1942, the first patient was treated for streptococcal sepsis with US-made penicillin produced by Merck & Co.[39] Half of the total supply produced at the time was used on that one patient, Anne Miller.[40] By June 1942, just enough US penicillin was available to treat ten patients.[41] In July 1943, the War Production Board drew up a plan for the mass distribution of penicillin stocks to Allied troops fighting in Europe.[42] 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. After a worldwide search in 1943, 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.[43] Pfizer scientist Jasper H. Kane suggested using a deep-tank fermentation method for producing large quantities of pharmaceutical-grade penicillin.[44][45] Large-scale production resulted from the development of a deep-tank fermentation plant by chemical engineer Margaret Hutchinson Rousseau.[46] As a direct result of the war and the War Production Board, by June 1945, over 646 billion units per year were being produced.[42]

    Penicillin was being mass-produced in 1944.
    World War II poster extolling use of penicillin

    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.[47] By 1943, 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 1945.[48][49][50] Florey had not patented penicillin, having been advised by Sir Henry Dale that doing so would be unethical.[37]

    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.[51] 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.[51] Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.[12]

    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, 1945.[52]

    Dorothy Hodgkin determined the chemical structure of penicillin.

    Structure determination and total synthesis
    Dorothy Hodgkin's model of penicillin's structure.

    The chemical structure of penicillin was first proposed by Edward Abraham in 1942[35] and was later confirmed in 1945 using X-ray crystallography by Dorothy Crowfoot Hodgkin, who was also working at Oxford.[53] 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 1957.[54][55][56] Sheehan had started his studies into penicillin synthesis in 1948, 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.[56][57] 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.[56][58][59] Attaching different groups to the 6-APA 'nucleus' of penicillin allowed the creation of new forms of 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 active 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 1961. 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.[60]

    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 important, the cephalosporins, still retain it at the center of their structures.[61]

    Production
    A 1957 fermentor (bioreactor) used to grow Penicillium mould.

    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.

    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.

    Biosynthesis
    Penicillin G biosynthesis

    Overall, there are three main and important steps to the biosynthesis of penicillin G (benzylpenicillin).

    • The first step is the condensation of three amino acids—L-α-aminoadipic acid, L-cysteine, L-valine into a tripeptide.[62][63][64] Before condensing into the tripeptide, the amino acid L-valine must undergo epimerization to become D-valine.[65][66] 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 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.[62][63] Isopenicillin N is a very weak intermediate, because it does not show strong antibiotic activity.[65]
    • 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.[62]
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    See also

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    Further reading
    • Nicolaou KC, Corey EJ (1996). Classics in Total Synthesis : Targets, Strategies, Methods (5. repr. ed.). Weinheim: VCH. ISBN 978-3-527-29284-4.
    • Dürckheimer W, Blumbach J, Lattrell R, Scheunemann KH (March 1, 1985). "Recent Developments in the Field of β-Lactam Antibiotics". Angewandte Chemie International Edition in English. 24 (3): 180–202. doi:10.1002/anie.198501801.
    • Hamed RB, Gomez-Castellanos JR, Henry L, Ducho C, McDonough MA, Schofield CJ (January 2013). "The enzymes of β-lactam biosynthesis". Natural Product Reports. 30 (1): 21–107. doi:10.1039/c2np20065a. PMID 23135477.
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