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Penicillin

From Academic Kids

For the Japanese rock band, see Penicillin (band).

Penicillin is a β-lactam antibiotic used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. The name "penicillin" can either refer to several variants of penicillin available, or to the group of antibiotics derived from the penicillins.

Penicillin nucleus
Penicillin nucleus

Penicillin has a molecular formula R-C9H11N2O4S, where R is a variable side chain.

Contents

History

Penicillin was originally isolated from the Penicillium chrysogenum (formerly Penicillium notatum) mould. The antibiotic effect was originally discovered by a young French medical student Ernest Duchesne studying Penicillium glaucum in 1896, although his work had no lasting consequences.

It was serendipitously rediscovered by Alexander Fleming in 1928, who noticed a halo of inhibition of bacterial growth around a contaminant blue-green mould on a Staphylococcus culture. Fleming concluded that the mould was releasing a substance that was inhibiting bacterial growth. He grew a pure culture and discovered that the fungus was Penicillium notatum — he later named the bacterial inhibiting substance penicillin after the Penicillium notatum that released it. Fleming was convinced after conducting some more experiments that penicillin could not last long enough in the human body to kill pathogenic bacteria and stopped studying penicillin after 1931. It would prove to be the discovery that changed modern medicine. In 1939, Howard Walter Florey and a team of researchers at Oxford University made significant progress in showing Penicillin's in vivo ability to kill infectious bacteria. This eventually led to commercial production of penicillin and the belief that modern medicine has led the world in an era free of diseases.

During World War II, penicillin made a major difference in the number of deaths and amputations caused by infected wounds amongst Allied forces. 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. Penicillins are actively secreted and about 80% of a penicillin dose is cleared within three to four hours of administration. During those times it became common procedure to collect the urine from patients being treated so that the penicillin could be isolated and reused. (Silverthorn, 2004)

This was not a satisfactory solution, however, so researchers looked for a way to slow penicillin secretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for secretion such that the transporter would preferentially secrete the competitive inhibitor. The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are concomitantly administered, probenecid competitively inhibits the secretion of penicillin, increasing its concentration and prolonging its activity. The advent of mass-production techniques and semi-synthetic penicillins solved supply issues, and this use of probenecid declined. (Silverthorn, 2004) Probenecid is still clinically useful, however, for certain infections requiring particularly high concentrations of penicillins. (Rossi, 2004)

The chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin in the early 1940s, enabling synthetic production. A team of Oxford research scientists led by Australian Howard Walter Florey and including Ernst Boris Chain and Norman Heatley discovered a method of mass producing the drug. Florey and Chain shared the 1945 Nobel prize in medicine with Fleming for this work. Penicillin has since become the most widely used antibiotic to date and is still used for many Gram-positive bacterial infections.

Mode of action

Main article: beta-lactam antibiotic

Penicillin and other β-lactam antibiotics work by inhibiting the formation of peptidoglycan cross links in the bacterial cell wall. The beta-lactam moiety of penicillin binds to the enzyme that links the peptidoglycan molecules in bacteria, and this weakens the cell wall of the bacterium when it multiplies (in other words, the antibiotic causes cell cytolysis or death when the bacterium tries to divide).

Variants

Benzathine penicillin

Benzathine penicillin is slowly absorbed into the circulation, after intramuscular injection, and hydrolysed to benzylpenicillin in vivo. It is the drug-of-choice when prolonged low concentrations of benzylpenicillin are required and appropriate, allowing prolonged antibiotic action over 2–4 weeks after a single IM dose. It is marketed by Wyeth under the trade name Bicillin®.

Specific indications for benzathine pencillin include: (Rossi, 2004)

Benzylpenicillin (penicillin G)

Missing image
Penicillin-G.png
Penicillin G (Benzylpenicillin)

Benzylpenicillin, commonly known as penicillin G, is the gold standard penicillin. Penicillin G is typically given by a parenteral route of administration because it is unstable to the hydrochloric acid of the stomach. Because the drug is given parenterally, higher tissue concentrations of penicillin G can be achieved than is possible with phenoxymethylpenicillin. These higher concentrations translate to increased antibacterial activity.

Specific indications for benzylpenicillin include: (Rossi, 2004)

Phenoxymethylpenicillin (penicillin V)

Phenoxymethylpenicillin, commonly known as penicillin V, is the orally-active form of penicillin. It is less active than benzylpenicillin, however, and is only appropriate in conditions where high tissue concentrations are not required.

Specific indications for phenoxymethylpenicillin include: (Rossi, 2004)

Procaine penicillin

Procaine penicillin is a combination of benzylpenicillin with the local anaesthetic agent procaine. This combination is aimed at reducing the pain and discomfort associated with a large intramuscular injection of penicillin.

Specific indications for procaine penicillin include: (Rossi, 2004)

Resistance

Antibiotic resistance to penicillin is now common amongst many hospital acquired bacteria. The resistance to penicillin has been partly due to the rise of beta-lactamase producing bacteria which secrete an enzyme that breaks down the beta-lactam ring of penicillin, rendering it harmless to the bacteria. These bacteria may remain sensitive to other beta-lactam antibiotics. Resistance also arises through modifications to the bacterial cell wall; this resistance usually extends to other beta-lactam antibiotics.

Developments from penicillin

The narrow spectrum of activity of the penicillins, along with the poor activity of the orally-active phenoxymethylpenicillin, led to the search for derivatives of penicillin which could treat a wider range of infections.

The first real step forward was in the form of ampicillin. Ampicillin offered a broader spectrum of activity than either of the original penicillins and allowed doctors to treat a broader range of both Gram-positive and Gram-negative infections. Further developments led to amoxicillin, with improved duration-of-action.

Further development gave us flucloxacillin, important even now for its resistance to beta-lactamases produced by bacteria such as Staphylococcus species. It is still no match for MRSA (Methicillin Resistant Staphylococcus aureus).

The last in the line of true penicillins were the antipseudomonal penicillins, such as ticarcillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the beta-lactam ring was such that related antibiotics, including the mecillinams, the carbapenems and, most importantly, the cephalosporins, have it at the centre of their structures.

Biosynthesis

Missing image
Penicillin-biosynthesis.png
Penicillin biosynthesis

The precursor compound ACV-tripeptide (δ-(L-α-amino-adipate)-L-cysteine-D-valine) is biosynthesized in bacteria and fungi from the monomeric L-amino acids by the enzyme ACV-synthetase (EC 6.3.2.26), a nonribosomal peptide synthetase. The ACV-tripeptide is cyclized by isopenicillin-N-synthetase (EC 1.21.3.1) to isopenicillin N, thereby forming the beta-lactam nucleus. The isopenicillin N N-acyltransferase (EC 2.3.1.164) exchanges the sidechain, yielding a broad range of different penicillins depending on the utilized CoA-bound carboxylic acids. The synthesis of the cephalosporin-type antibiotics starts with isopenicillin N. (Moss, 2002)

See also

References

da:Penicillin de:Penicillin es:Penicilina eo:Penicilino fr:Pnicilline he:פניצילין hu:Penicillin is:Penisilln ja:ペニシリン ko:페니실린 nl:Penicilline pl:Penicylina pt:Penicilina fi:Penisilliini sv:Penicillin zh:青霉素

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