Penicillin

Penicillin

Overview

Penicillin is a group of antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...

s derived from Penicillium
Penicillium
Penicillium is a genus of ascomycetous fungi of major importance in the natural environment as well as food and drug production. Members of the genus produce penicillin, a molecule that is used as an antibiotic, which kills or stops the growth of certain kinds of bacteria inside the body...

fungi. They include penicillin G
Benzylpenicillin
Benzylpenicillin, commonly known as penicillin G, is the gold standard type of penicillin. 'G' in the name 'Penicillin G' refers to 'Gold Standard'. Penicillin G is typically given by a parenteral route of administration because it is unstable in the hydrochloric acid of the stomach...

, procaine penicillin
Procaine benzylpenicillin
Procaine benzylpenicillin , also known as procaine penicillin, is a form of penicillin which is a combination of benzylpenicillin and the local anaesthetic agent procaine...

, benzathine penicillin
Benzathine benzylpenicillin
Benzathine benzylpenicillin is a form of penicillin also known as benzathine penicillin. It is slowly absorbed into the circulation, after intramuscular injection, and hydrolysed to benzylpenicillin in vivo...

, and penicillin V
Phenoxymethylpenicillin
Phenoxymethylpenicillin, commonly known as penicillin V, is a penicillin antibiotic that is orally active. It is less active than benzylpenicillin against Gram-negative bacteria. Phenoxymethylpenicillin is more acid-stable than benzylpenicillin, which allows it to be given orally...

.
Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases, such as syphilis
Syphilis
Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum. The primary route of transmission is through sexual contact; however, it may also be transmitted from mother to fetus during pregnancy or at birth, resulting in congenital syphilis...

, and infections caused by staphylococci
Staphylococcus
Staphylococcus is a genus of Gram-positive bacteria. Under the microscope they appear round , and form in grape-like clusters....

  and streptococci
Streptococcus
Streptococcus is a genus of spherical Gram-positive bacteria belonging to the phylum Firmicutes and the lactic acid bacteria group. Cellular division occurs along a single axis in these bacteria, and thus they grow in chains or pairs, hence the name — from Greek στρεπτος streptos, meaning...

. Penicillins are still widely used today, though many types of bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

 are now resistant
Antibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...

. All penicillins are β-lactam antibiotic
Beta-lactam antibiotic
β-Lactam antibiotics are a broad class of antibiotics, consisting of all antibiotic agents that contains a β-lactam nucleus in its molecular structure. This includes penicillin derivatives , cephalosporins , monobactams, and carbapenems...

s and are used in the treatment of bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

l infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

s caused by susceptible, usually Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...

, organisms.

The term "penicillin" is often used generically to refer to benzylpenicillin
Benzylpenicillin
Benzylpenicillin, commonly known as penicillin G, is the gold standard type of penicillin. 'G' in the name 'Penicillin G' refers to 'Gold Standard'. Penicillin G is typically given by a parenteral route of administration because it is unstable in the hydrochloric acid of the stomach...

 (penicillin G), procaine benzylpenicillin
Procaine benzylpenicillin
Procaine benzylpenicillin , also known as procaine penicillin, is a form of penicillin which is a combination of benzylpenicillin and the local anaesthetic agent procaine...

 (procaine penicillin), benzathine benzylpenicillin
Benzathine benzylpenicillin
Benzathine benzylpenicillin is a form of penicillin also known as benzathine penicillin. It is slowly absorbed into the circulation, after intramuscular injection, and hydrolysed to benzylpenicillin in vivo...

 (benzathine penicillin), and phenoxymethylpenicillin
Phenoxymethylpenicillin
Phenoxymethylpenicillin, commonly known as penicillin V, is a penicillin antibiotic that is orally active. It is less active than benzylpenicillin against Gram-negative bacteria. Phenoxymethylpenicillin is more acid-stable than benzylpenicillin, which allows it to be given orally...

 (penicillin V).

Procaine penicillin and benzathine penicillin have the same antibacterial activity as benzylpenicillin but act for a longer period.
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Encyclopedia

Penicillin is a group of antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...

s derived from Penicillium
Penicillium
Penicillium is a genus of ascomycetous fungi of major importance in the natural environment as well as food and drug production. Members of the genus produce penicillin, a molecule that is used as an antibiotic, which kills or stops the growth of certain kinds of bacteria inside the body...

fungi. They include penicillin G
Benzylpenicillin
Benzylpenicillin, commonly known as penicillin G, is the gold standard type of penicillin. 'G' in the name 'Penicillin G' refers to 'Gold Standard'. Penicillin G is typically given by a parenteral route of administration because it is unstable in the hydrochloric acid of the stomach...

, procaine penicillin
Procaine benzylpenicillin
Procaine benzylpenicillin , also known as procaine penicillin, is a form of penicillin which is a combination of benzylpenicillin and the local anaesthetic agent procaine...

, benzathine penicillin
Benzathine benzylpenicillin
Benzathine benzylpenicillin is a form of penicillin also known as benzathine penicillin. It is slowly absorbed into the circulation, after intramuscular injection, and hydrolysed to benzylpenicillin in vivo...

, and penicillin V
Phenoxymethylpenicillin
Phenoxymethylpenicillin, commonly known as penicillin V, is a penicillin antibiotic that is orally active. It is less active than benzylpenicillin against Gram-negative bacteria. Phenoxymethylpenicillin is more acid-stable than benzylpenicillin, which allows it to be given orally...

.
Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases, such as syphilis
Syphilis
Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum. The primary route of transmission is through sexual contact; however, it may also be transmitted from mother to fetus during pregnancy or at birth, resulting in congenital syphilis...

, and infections caused by staphylococci
Staphylococcus
Staphylococcus is a genus of Gram-positive bacteria. Under the microscope they appear round , and form in grape-like clusters....

  and streptococci
Streptococcus
Streptococcus is a genus of spherical Gram-positive bacteria belonging to the phylum Firmicutes and the lactic acid bacteria group. Cellular division occurs along a single axis in these bacteria, and thus they grow in chains or pairs, hence the name — from Greek στρεπτος streptos, meaning...

. Penicillins are still widely used today, though many types of bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

 are now resistant
Antibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...

. All penicillins are β-lactam antibiotic
Beta-lactam antibiotic
β-Lactam antibiotics are a broad class of antibiotics, consisting of all antibiotic agents that contains a β-lactam nucleus in its molecular structure. This includes penicillin derivatives , cephalosporins , monobactams, and carbapenems...

s and are used in the treatment of bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

l infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

s caused by susceptible, usually Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...

, organisms.

Medical uses


The term "penicillin" is often used generically to refer to benzylpenicillin
Benzylpenicillin
Benzylpenicillin, commonly known as penicillin G, is the gold standard type of penicillin. 'G' in the name 'Penicillin G' refers to 'Gold Standard'. Penicillin G is typically given by a parenteral route of administration because it is unstable in the hydrochloric acid of the stomach...

 (penicillin G), procaine benzylpenicillin
Procaine benzylpenicillin
Procaine benzylpenicillin , also known as procaine penicillin, is a form of penicillin which is a combination of benzylpenicillin and the local anaesthetic agent procaine...

 (procaine penicillin), benzathine benzylpenicillin
Benzathine benzylpenicillin
Benzathine benzylpenicillin is a form of penicillin also known as benzathine penicillin. It is slowly absorbed into the circulation, after intramuscular injection, and hydrolysed to benzylpenicillin in vivo...

 (benzathine penicillin), and phenoxymethylpenicillin
Phenoxymethylpenicillin
Phenoxymethylpenicillin, commonly known as penicillin V, is a penicillin antibiotic that is orally active. It is less active than benzylpenicillin against Gram-negative bacteria. Phenoxymethylpenicillin is more acid-stable than benzylpenicillin, which allows it to be given orally...

 (penicillin V).

Procaine penicillin and benzathine penicillin have the same antibacterial activity as benzylpenicillin but act for a longer period. Phenoxymethylpenicillin is less active against Gram-negative bacteria than benzylpenicillin. Benzylpenicillin, procaine penicillin and benzathine penicillin are given by injection (parenterally), but phenoxymethylpenicillin is given orally.

Adverse effects



Common adverse drug reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

s (≥1% of patients) associated with use of the penicillins include diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

, hypersensitivity
Hypersensitivity
Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...

, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

, rash, neurotoxicity
Neurotoxicity
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...

, urticaria
Urticaria
Urticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...

, and superinfection
Superinfection
In virology, superinfection is the process by which a cell, that has previously been infected by one virus, gets coinfected with a different strain of the virus, or another virus at a later point in time. Viral superinfections of serious conditions can lead to resistant strains of the virus, which...

 (including candidiasis
Candidiasis
Thrush redirects here. For the hoof infection see Thrush .Candidiasis or thrush is a fungal infection of any of the Candida species , of which Candida albicans is the most common...

). Infrequent adverse effects (0.1–1% of patients) include fever, vomiting, erythema
Erythema
Erythema is redness of the skin, caused by hyperemia of the capillaries in the lower layers of the skin. It occurs with any skin injury, infection, or inflammation...

, dermatitis
Dermatitis
-Etymology:Dermatitis derives from Greek derma "skin" + -itis "inflammation" and genetic disorder.-Terminology:There are several different types of dermatitis. The different kinds usually have in common an allergic reaction to specific allergens. The term may describe eczema, which is also called...

, angioedema
Angioedema
Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...

, seizures (especially in epileptics), and pseudomembranous colitis
Pseudomembranous colitis
Pseudomembranous colitis, a cause of antibiotic-associated diarrhea , is an infection of the colon. It is often, but not always, caused by the bacterium Clostridium difficile. Because of this, the informal name C. difficile colitis is also commonly used. The illness is characterized by...

.

Mechanism of action



Bacteria constantly remodel their peptidoglycan
Peptidoglycan
Peptidoglycan, also known as murein, is a polymer consisting of sugars and amino acids that forms a mesh-like layer outside the plasma membrane of bacteria , forming the cell wall. The sugar component consists of alternating residues of β- linked N-acetylglucosamine and N-acetylmuramic acid...

 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
Peptidoglycan
Peptidoglycan, also known as murein, is a polymer consisting of sugars and amino acids that forms a mesh-like layer outside the plasma membrane of bacteria , forming the cell wall. The sugar component consists of alternating residues of β- linked N-acetylglucosamine and N-acetylmuramic acid...

 cross-link
Cross-link
Cross-links are bonds that link one polymer chain to another. They can be covalent bonds or ionic bonds. "Polymer chains" can refer to synthetic polymers or natural polymers . When the term "cross-linking" is used in the synthetic polymer science field, it usually refers to the use of...

s in the bacterial cell wall
Cell wall
The cell wall is the tough, usually flexible but sometimes fairly rigid layer that surrounds some types of cells. It is located outside the cell membrane and provides these cells with structural support and protection, and also acts as a filtering mechanism. A major function of the cell wall is to...

, but have no direct effect on cell wall degradation
Degradation
Degradation may refer to;* Biodegradation, the processes by which organic substances are broken down by living organisms* Cashiering or degradation ceremony, a ritual performed when cleric is deprived of office or a knight is stripped of the honour...

. The β-lactam
Beta-lactam
A β-lactam ring, is a four-membered lactam. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl...

 moiety (functional group
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...

) of penicillin binds to the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 (DD-transpeptidase) that links the peptidoglycan molecules in bacteria. The enzymes that hydrolyze the peptidoglycan cross-links continue to function, which weakens the cell wall of the bacterium (in other words, the antibiotic causes cytolysis
Cytolysis
Cytolysis, or osmotic lysis, occurs when a cell bursts due to an osmotic imbalance that has caused excess water to move into the cell. It occurs in a hypotonic environment, where water diffuses into the cell and causes its volume to increase. If the volume of water exceeds the cell membrane's...

 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. This imbalance between cell wall production and degradation is responsible for the rapid cell-killing action of this class of drugs, even in the absence of cell division. In addition, the relatively small size of the penicillin molecule allows it to penetrate deeply into the cell wall, affecting its entire depth. This is in contrast to the other major class of anitbiotics that inhibit cell wall synthesis, the glycopeptide
Glycopeptide
Glycopeptides are peptides that contain carbohydrate moieties covalently attached to the side chains of the amino acid residues that constitute the peptide. Over the past few decades it has been recognised that glycans on cell surface and those bound to proteins play a critical role in biology...

 antibiotics (which includes vancomycin
Vancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...

 and teicoplanin
Teicoplanin
Teicoplanin is an antibiotic used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. It is a glycopeptide antibiotic extracted from Actinoplanes teichomyceticus, with a similar...

).

Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...

 bacteria are called protoplast
Protoplast
Protoplast, from the ancient Greek πρῶτον + verb πλάθω or πλάττω , initially referred to the first organized body of a species.Protoplast has several biological definitions:...

s when they lose their cell walls. Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...

 bacteria do not lose their cell walls completely and are called spheroplast
Spheroplast
A spheroplast is a cell from which the cell wall has been almost completely removed, as by the action of penicillin. The name stems from the fact that after a microbe's cell wall is digested, membrane tension causes the cell to acquire a characteristic spherical shape...

s 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
Minimum Bactericidal Concentration
The Minimum Bactericidal Concentration is the lowest concentration of antibiotic required to kill the germ. Not as commonly seen as the Minimum inhibitory concentration . It can be determined from broth dilution MIC tests by subculturing to agar media without antibiotics...

 for susceptible organisms.

Penicillins, like other β-lactam antibiotic
Beta-lactam antibiotic
β-Lactam antibiotics are a broad class of antibiotics, consisting of all antibiotic agents that contains a β-lactam nucleus in its molecular structure. This includes penicillin derivatives , cephalosporins , monobactams, and carbapenems...

s, block not only the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosynthetic
Photosynthesis
Photosynthesis is a chemical process that converts carbon dioxide into organic compounds, especially sugars, using the energy from sunlight. Photosynthesis occurs in plants, algae, and many species of bacteria, but not in archaea. Photosynthetic organisms are called photoautotrophs, since they can...

 organelle
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....

s of the glaucophyte
Glaucophyte
The glaucophytes, also known as glaucocystophytes or glaucocystids, are a small group of freshwater microscopic algae. Together with the red algae and green algae plus land plants , they form the Archaeplastida...

s, and the division of chloroplast
Chloroplast
Chloroplasts are organelles found in plant cells and other eukaryotic organisms that conduct photosynthesis. Chloroplasts capture light energy to conserve free energy in the form of ATP and reduce NADP to NADPH through a complex set of processes called photosynthesis.Chloroplasts are green...

s of bryophyte
Bryophyte
Bryophyte is a traditional name used to refer to all embryophytes that do not have true vascular tissue and are therefore called 'non-vascular plants'. Some bryophytes do have specialized tissues for the transport of water; however since these do not contain lignin, they are not considered to be...

s. In contrast, they have no effect on the plastid
Plastid
Plastids are major organelles found in the cells of plants and algae. Plastids are the site of manufacture and storage of important chemical compounds used by the cell...

s of the highly developed vascular plant
Vascular plant
Vascular plants are those plants that have lignified tissues for conducting water, minerals, and photosynthetic products through the plant. Vascular plants include the clubmosses, Equisetum, ferns, gymnosperms and angiosperms...

s. This supports the endosymbiotic theory
Endosymbiotic theory
The endosymbiotic theory concerns the mitochondria, plastids , and possibly other organelles of eukaryotic cells. According to this theory, certain organelles originated as free-living bacteria that were taken inside another cell as endosymbionts...

 of the evolution
Evolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...

 of plastid division in land plant
Plant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...

s.

Structure



The term "penam
Penam
Penams are a subclass of the broader β-lactam family of antibiotics and related compounds. Penams contain a β-lactam ring fused to a 5-membered ring, where one of the atoms in the ring is a sulfur and the ring is fully saturated. Penicillin is a member of this family of compounds....

" is used to describe the core skeleton of a member of a penicillin antibiotic. This skeleton has the molecular formula R-C9H11N2O4S, where R is a variable side chain
Side chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...

.

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
Cloxacillin
Cloxacillin is a semisynthetic antibiotic in the same class as penicillin. Cloxacillin was discovered and developed by Beecham. It is sold under a number of trade names, including Cloxapen, Cloxacap, Tegopen and Orbenin....

 has a molar mass of 476 g/mol and dicloxacillin
Dicloxacillin
Dicloxacillin is a narrow-spectrum beta-lactam antibiotic of the penicillin class. It is used to treat infections caused by susceptible Gram-positive bacteria. It is active against beta-lactamase-producing organisms such as Staphylococcus aureus, which would otherwise be resistant to most...

 has a molar mass of 492 g/mol.

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
    Tripeptide
    A tripeptide is a peptide consisting of three amino acids joined by peptide bonds.Examples of tripeptides are:*Eisenin is a peptide with immunological activity that is isolated from the Japanese marine alga, Eisenia bicyclis, which more commonly is known as, Arame*GHK-Cu is a human copper binding...

    . 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
    Nonribosomal peptide
    Nonribosomal peptides are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacteria inside these organisms...

     or NRPS.
  • The second step in the biosynthesis of penicillin G is the oxidative
    Redox
    Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....

     conversion of linear ACV into the bicyclic
    Bicyclic molecule
    A bicyclic molecule is a molecule that features two fused rings. Bicyclic molecules occur widely in organic and inorganic compounds.Fusion of the rings can occur in three ways:...

     intermediate isopenicillin N by isopenicillin-N synthase
    Isopenicillin-N synthase
    Isopenicillin-N synthase is a non-heme iron-dependent enzyme belonging to the oxidoreductase family. This enzyme catalyzes the formation of isopenicillin-N from δ--L-cysteinyl-D-valine ....

     (IPNS), which is encoded by the gene pcbC. Isopenicillin N is a very weak intermediate, because it does not show strong antibiotic activity.
  • The final step is an transamidation by isopenicillin-N N-acyltransferase
    Isopenicillin-N N-acyltransferase
    In enzymology, an isopenicillin-N N-acyltransferase is an enzyme that catalyzes the chemical reactionThe 3 substrates of this enzyme are phenylacetyl-CoA, isopenicillin N, and H2O, whereas its 3 products are CoA, penicillin G, and L-2-aminohexanedioate....

    , in which the α-aminoadipyl side-chain of isopenicillin N is removed and exchanged for a phenylacetyl
    Phenylacetic acid
    Phenylacetic acid is an organic compound containing a phenyl functional group and a carboxylic acid functional group. It is a white solid with a disagreeable odor...

     side-chain. This reaction is encoded by the gene penDE, which is unique in the process of obtaining penicillins.

Production


Penicillin is a secondary metabolite
Secondary metabolism
Secondary metabolism is a term for pathways and small molecule products of metabolism that are not absolutely required for the survival of the organism. Examples of the products include antibiotics and pigments. To distinguish non-secondary metabolism, the term basic metabolism is sometimes used...

 of certain species of Penicillium
Penicillium
Penicillium is a genus of ascomycetous fungi of major importance in the natural environment as well as food and drug production. Members of the genus produce penicillin, a molecule that is used as an antibiotic, which kills or stops the growth of certain kinds of bacteria inside the body...

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
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...

 → homocitrate
Homocitric acid
Homocitric acid is an organic compound with the formula HOC. This tricarboxylic acid occurs naturally as a component of the iron-molybdenum cofactor of certain nitrogenase proteins...

 → L-α-aminoadipic acid → L-lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....

 + β-lactam
Beta-lactam
A β-lactam ring, is a four-membered lactam. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl...



The by-product, -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
Fed-batch
A fed-batch is a biotechnological batch process which is based on feeding of a growth limiting nutrient substrate to a culture.The fed-batch strategy is typically used in bio-industrial processes to reach a high cell density in the bioreactor....

 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
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

 inhibits penicillin production, whereas lactose
Lactose
Lactose is a disaccharide sugar that is found most notably in milk and is formed from galactose and glucose. Lactose makes up around 2~8% of milk , although the amount varies among species and individuals. It is extracted from sweet or sour whey. The name comes from or , the Latin word for milk,...

 does not. The pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...

 and the levels of nitrogen, lysine, phosphate, and oxygen of the batches must also be carefully controlled.

The biotechnological
Biotechnology
Biotechnology is a field of applied biology that involves the use of living organisms and bioprocesses in engineering, technology, medicine and other fields requiring bioproducts. Biotechnology also utilizes these products for manufacturing purpose...

 method of directed evolution
Directed evolution
thumb|250px|right|An example of a possible round to evolve a protein based fluorescent sensor for a specific analyte using two consecutive FACS sortings...

 has been applied to produce by mutation a large number of Penicillium strains. These techniques include error-prone PCR
Polymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....

, DNA shuffling
DNA shuffling
DNA shuffling is a way to rapidly propagate beneficial mutations in a directed evolution experiment. It is used to rapidly increase DNA library size. -Procedure:DNAse I is first used to fragment a set of parent genes into pieces of 50-100 bp in length...

, , and strand-overlap PCR.

Discovery



The discovery of penicillin is attributed to Scottish
Scotland
Scotland is a country that is part of the United Kingdom. Occupying the northern third of the island of Great Britain, it shares a border with England to the south and is bounded by the North Sea to the east, the Atlantic Ocean to the north and west, and the North Channel and Irish Sea to the...

 scientist and Nobel laureate Alexander Fleming
Alexander Fleming
Sir Alexander Fleming was a Scottish biologist and pharmacologist. He wrote many articles on bacteriology, immunology, and chemotherapy...

 in 1928. He showed that, if Penicillium notatum were grown in the appropriate substrate, it would exude a substance with antibiotic properties, which he dubbed penicillin. This serendipitous
Serendipity
Serendipity means a "happy accident" or "pleasant surprise"; specifically, the accident of finding something good or useful without looking for it. The word has been voted as one of the ten English words hardest to translate in June 2004 by a British translation company. However, due to its...

 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
Howard Walter Florey
Howard Walter Florey, Baron Florey OM FRS was an Australian pharmacologist and pathologist who shared the Nobel Prize in Physiology or Medicine in 1945 with Sir Ernst Boris Chain and Sir Alexander Fleming for his role in the making of penicillin. Florey's discoveries are estimated to have saved...

, together with the German Nobel laureate Ernst Chain and the English biochemist Norman Heatley
Norman Heatley
Norman George Heatley was a member of the team of Oxford University scientists who developed penicillin.He was born in Woodbridge, Suffolk, and as a boy was an enthusiastic sailor of a small boat on the River Deben; an experience which gave him a lifelong love of sailing...

.

However, several others reported the bacteriostatic effects of Penicillium earlier than Fleming. The use of bread with a blue mould (presumed to be 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
Royal Society
The Royal Society of London for Improving Natural Knowledge, known simply as the Royal Society, is a learned society for science, and is possibly the oldest such society in existence. Founded in November 1660, it was granted a Royal Charter by King Charles II as the "Royal Society of London"...

 in 1875, by John Tyndall
John Tyndall
John Tyndall FRS was a prominent Irish 19th century physicist. His initial scientific fame arose in the 1850s from his study of diamagnetism. Later he studied thermal radiation, and produced a number of discoveries about processes in the atmosphere...

. Joaquim Monteiro Caminhoá, Professor of Botany and Zoology of the Faculty of Medicine of Rio de Janeiro, Brazil, also recognised the antibiotic activity of Penicillium and other fungi in 1877. In his book, "Elements of General and Medical Botany" (under a section titled 'Useful fungi, harmful and curious'), he stated:
O bolor (Penicillium infestans, Penicillium glaucum, fig 1680, Ascophora e tantos outros) é util porque nutre-se decompondo e destruindo as materias organicas em putrefacção, e de modo que o cheiro infecto não se produz, em via de regra, ou produz-se em proporções infinitamente menores.
[Translation: "The mold (Penicillium infestans, Penicillium glaucum, figure 1680, Ascophora and many others) is useful because it feeds on decaying organic matter and destroys putrifaction so that, as a rule, the odour of infection does not occur, or is produced in infinitely smaller amounts."]


Ernest Duchesne
Ernest Duchesne
Ernest Duchesne was a French physician who noted that certain moulds kill bacteria. He made this discovery 32 years before Alexander Fleming discovered the antibiotic properties of penicillin, a substance derived from those moulds, but his research went unnoticed.-Life and work: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
San Juan De Dios Educational Foundation
San Juan de Dios Educational Foundation, Inc. is a private, non-stock, non-profit, joint institute of education and tertiary health sciences operating as a college and hospital within the City of Pasay, Philippines. Both the colleges and hospital are run by the Daughters of Charity.-History:The...

 in San José, Costa Rica, published the manuscripts of the Costa Rican scientist and medical doctor Clodomiro (Clorito) Picado Twight
Clodomiro Picado Twight
Clodomiro Picado Twight , also known as "Clorito Picado", was a Nicaraguan-born scientist, citizen of Costa Rica, who was recognized for his research and discoveries. He was pioneer in the researching snakes and serpent venoms; his internationally recognized achievement was the development of...

 (1887–1944). 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
French Academy of Sciences
The French Academy of Sciences is a learned society, founded in 1666 by Louis XIV at the suggestion of Jean-Baptiste Colbert, to encourage and protect the spirit of French scientific research...

, 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
Aseptic technique
Aseptic technique refers to a procedure that is performed under sterile conditions. This includes medical and laboratory techniques, such as with microbiological cultures. It includes techniques like flame sterilization...

. He found that it weakened the microbes, but then he dismissed the fungi.

These early investigations did not lead to the use of antibiotics to treat infection because they took place in obscure circumstances, and the idea that infections were caused by transmissible agents was not widely accepted at the time. Sterilization measures had been shown to limit the outbreak and spread of disease; however, the mechanism of transmission of disease by parasites, bacteria, viruses and other agents was unknown. In the late 19th century, there was increasing knowledge of the mechanisms by which living organisms become infected, how they manage infection once it has begun and, most importantly in the case of penicillin, the effect that natural and man-made agents could have on the progress of infection.

Fleming recounted that the date of his discovery of penicillin 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
London
London is the capital city of :England and the :United Kingdom, the largest metropolitan area in the United Kingdom, and the largest urban zone in the European Union by most measures. Located on the River Thames, London has been a major settlement for two millennia, its history going back to its...

 (now part of Imperial College), Fleming noticed a Petri dish containing Staphylococcus
Staphylococcus
Staphylococcus is a genus of Gram-positive bacteria. Under the microscope they appear round , and form in grape-like clusters....

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
Lysis
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....

 the bacteria. He grew a pure culture and discovered it was a Penicillium
Penicillium
Penicillium is a genus of ascomycetous fungi of major importance in the natural environment as well as food and drug production. Members of the genus produce penicillin, a molecule that is used as an antibiotic, which kills or stops the growth of certain kinds of bacteria inside the body...

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
Microbiological culture
A microbiological culture, or microbial culture, is a method of multiplying microbial organisms by letting them reproduce in predetermined culture media under controlled laboratory conditions. Microbial cultures are used to determine the type of organism, its abundance in the sample being tested,...

 of the Penicillium mould. Even in these early stages, penicillin was found to be most effective against Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...

 bacteria, and ineffective against Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...

 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
Haemophilus influenzae
Haemophilus influenzae, formerly called Pfeiffer's bacillus or Bacillus influenzae, Gram-negative, rod-shaped bacterium first described in 1892 by Richard Pfeiffer during an influenza pandemic. A member of the Pasteurellaceae family, it is generally aerobic, but can grow as a facultative anaerobe. H...

). After further experiments, Fleming was convinced 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
Sheffield Royal Infirmary
The Royal Infirmary was a hospital in Sheffield, South Yorkshire. The establishment opened in 1792 under the name Sheffield General Infirmary, renamed Royal Infirmary in 1897 and closed in 1980....

 in Sheffield
Sheffield
Sheffield is a city and metropolitan borough of South Yorkshire, England. Its name derives from the River Sheaf, which runs through the city. Historically a part of the West Riding of Yorkshire, and with some of its southern suburbs annexed from Derbyshire, the city has grown from its largely...

, attempted to use penicillin to treat sycosis barbae, eruptions 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
Howard Walter Florey
Howard Walter Florey, Baron Florey OM FRS was an Australian pharmacologist and pathologist who shared the Nobel Prize in Physiology or Medicine in 1945 with Sir Ernst Boris Chain and Sir Alexander Fleming for his role in the making of penicillin. Florey's discoveries are estimated to have saved...

 (later Baron Florey) and a team of researchers (Ernst Boris Chain
Ernst Boris Chain
Sir Ernst Boris Chain was a German-born British biochemist, and a 1945 co-recipient of the Nobel Prize for Physiology or Medicine for his work on penicillin.-Biography:...

, Arthur Duncan Gardner, Norman Heatley
Norman Heatley
Norman George Heatley was a member of the team of Oxford University scientists who developed penicillin.He was born in Woodbridge, Suffolk, and as a boy was an enthusiastic sailor of a small boat on the River Deben; an experience which gave him a lifelong love of sailing...

, M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn School of Pathology, University of Oxford
University of Oxford
The University of Oxford is a university located in Oxford, United Kingdom. It is the second-oldest surviving university in the world and the oldest in the English-speaking world. Although its exact date of foundation is unclear, there is evidence of teaching as far back as 1096...

 made significant progress in showing the in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

bactericidal action of penicillin. Their attempts to treat humans failed because of insufficient volumes of penicillin (the first patient treated was Reserve Constable Albert Alexander
Albert Alexander
Reserve Constable Albert Alexander was the first patient to be treated with injections of penicillin.Albert Alexander was a constable in the police force of the County of Oxford, England. In December 1940, Constable Alexander was accidentally scratched by a rose thorn in his mouth...

), but they proved it harmless and effective on mice.

Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary
Radcliffe Infirmary
The Radcliffe Infirmary was a hospital in central Oxford, England, located at the southern end of Woodstock Road on the western side, backing onto Walton Street. The Radcliffe Infirmary, named after physician John Radcliffe, opened in 1770 and was Oxford's first hospital...

 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. On March 14, 1942, John Bumstead and Orvan Hess
Orvan Hess
Orvan Walter Hess was a physician noted for his early use of penicillin and the development of the fetal heart monitor....

 saved a dying patient's life using penicillin.

Mass production


The chemical structure
Chemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...

 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
Ernst Boris Chain
Sir Ernst Boris Chain was a German-born British biochemist, and a 1945 co-recipient of the Nobel Prize for Physiology or Medicine for his work on penicillin.-Biography:...

 and Norman Heatley
Norman Heatley
Norman George Heatley was a member of the team of Oxford University scientists who developed penicillin.He was born in Woodbridge, Suffolk, and as a boy was an enthusiastic sailor of a small boat on the River Deben; an experience which gave him a lifelong love of sailing...

 devised a method of mass-producing the drug. Florey and Chain shared the 1945 Nobel Prize in Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...

 with Fleming for their work. After World War II, Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...

 was the first country to make the drug available for civilian use. Chemist John C. Sheehan
John C. Sheehan
John Clark Sheehan was an American organic chemist whose work on synthetic penicillin led to tailor-made forms of the drug. After nine years of hard work at the Massachusetts Institute of Technology , he became the first to discover a practical method for synthesizing penicillin V...

 at MIT completed the first total synthesis
Total synthesis
In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...

 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.
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...

 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. In July 1943, the War Production Board
War Production Board
The War Production Board was established as a government agency on January 16, 1942 by executive order of Franklin D. Roosevelt.The purpose of the board was to regulate the production and allocation of materials and fuel during World War II in the United States...

 drew up a plan for the mass distribution of penicillin stocks to Allied troops fighting in Europe. A moldy cantaloupe
Cantaloupe
"Rockmelon" redirects here, for the band see Rockmelons. See also Cantaloupe .Cantaloupe refers to a variety of Cucumis melo, a species in the family Cucurbitaceae which includes nearly all melons and squashes. Cantaloupes range in size from...

 in a Peoria, Illinois, market in 1943 was found to contain the best and highest-quality penicillin after a worldwide search. The discovery of the cantaloupe, and the results of fermentation research on corn steep liquor
Corn steep liquor
Corn steep liquor is a by-product of corn wet-milling. It is an important constituent of some growth media. It was used in the culturing of Penicillium during research into penicillin, by American microbiologist Andrew J. Moyer. It is an excellent source of organic nitrogen. ....

 at the Northern Regional Research Laboratory at Peoria, Illinois
National Center for Agricultural Utilization Research
The National Center for Agricultural Utilization Research is an United States Department of Agriculture laboratory center in 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
Margaret Hutchinson Rousseau
Margaret Hutchinson Rousseau was a chemical engineer who designed the first commercial penicillin production plant. She was also the first female member of the American Institute of Chemical Engineers.-Life:...

. As a direct result of the war and the War Production Board, by June 1945, over 646 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.
During World War II
World War II
World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...

, penicillin made a major difference in the number of deaths and amputations caused by infected wounds among Allied
Allies of World War II
The Allies of World War II were the countries that opposed the Axis powers during the Second World War . Former Axis states contributing to the Allied victory are not considered Allied states...

 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
Clearance (medicine)
In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics...

 of the drug, necessitating frequent dosing. 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. 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
Uricosuric
Uricosuric medications are substances that increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. In general, this effect is achieved by action on the proximal tubule...

 agent probenecid
Probenecid
Probenecid is a uricosuric drug that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.Probenecid was developed as an alternative to caronamide...

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

Unethical experimentation


In a 1946 to 1948 study in Guatemala
Guatemala syphilis experiment
The syphilis experiments in Guatemala were United States-led human experiments conducted in Guatemala from 1946 to 1948, during the administration of President Truman and President Juan José Arévalo with the cooperation of some Guatemalan health ministries and officials...

, U.S. researchers used prostitutes to infect prison inmates, insane asylum patients, and Guatemalan soldiers with syphilis and other sexually transmitted disease
Sexually transmitted disease
Sexually transmitted disease , also known as a sexually transmitted infection or venereal disease , is an illness that has a significant probability of transmission between humans by means of human sexual behavior, including vaginal intercourse, oral sex, and anal sex...

s (STDs), to test the effectiveness of penicillin in treating such diseases. They later tried infecting people with "direct inoculations made from syphilis bacteria poured into the men's penises and on forearms and faces that were slightly abraded . . . or in a few cases through spinal punctures". Approximately 1300 people were infected as part of the study (including orphan
Orphan
An orphan is a child permanently bereaved of or abandoned by his or her parents. In common usage, only a child who has lost both parents is called an orphan...

 children). The study was sponsored by the Public Health Service, the National Institutes of Health and the Pan American Health Sanitary Bureau (now the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

's Pan American Health Organization) and the Guatemalan government. The team was led by John Charles Cutler
John Charles Cutler
John Charles Cutler, M.D. was a senior surgeon, and the acting chief of the venereal disease program in the United States Public Health Service....

, who later participated in the Tuskegee syphilis experiments. Cutler chose to do the study in Guatemala because he would not have been permitted to do it in the United States. The Presidential Commission for the Study of Bioethical Issues recently determined that 83 people died; however, it was not possible to determine whether the experiments were the direct cause of death.

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
6-APA
6-APA is the chemical compound -6-aminopenicillanic acid.-Use:6-APA is the core of penicillins. It is obtained from the fermentation brew of the Penicillium mold and used as the main starting block for the preparation of numerous semisynthetic penicillins.-Manufacture:This useful compound is made...

, the nucleus of penicillin, allowed for the preparation of semisynthetic penicillins, with various improvements over benzylpenicillin
Benzylpenicillin
Benzylpenicillin, commonly known as penicillin G, is the gold standard type of penicillin. 'G' in the name 'Penicillin G' refers to 'Gold Standard'. Penicillin G is typically given by a parenteral route of administration because it is unstable in the hydrochloric acid of the stomach...

 (bioavailability, spectrum, stability, tolerance).

The first major development was ampicillin
Ampicillin
Ampicillin is a beta-lactam antibiotic that has been used extensively to treat bacterial infections since 1961. Until the introduction of ampicillin by the British company Beecham, penicillin therapies had only been effective against Gram-positive organisms such as staphylococci and streptococci...

, which offered a broader spectrum of activity than either of the original penicillins. Further development yielded β-lactamase-resistant penicillins, including flucloxacillin
Flucloxacillin
Flucloxacillin or floxacillin is a narrow-spectrum beta-lactam antibiotic of the penicillin class. It is used to treat infections caused by susceptible Gram-positive bacteria. Unlike other penicillins, flucloxacillin has activity against beta-lactamase-producing organisms such as Staphylococcus...

, dicloxacillin
Dicloxacillin
Dicloxacillin is a narrow-spectrum beta-lactam antibiotic of the penicillin class. It is used to treat infections caused by susceptible Gram-positive bacteria. It is active against beta-lactamase-producing organisms such as Staphylococcus aureus, which would otherwise be resistant to most...

, and methicillin
Methicillin
Meticillin or methicillin is a narrow-spectrum beta-lactam antibiotic of the penicillin class. It should not be confused with the antibiotic metacycline.-History:Methicillin was developed by Beecham in 1959...

. These were significant for their activity against β-lactamase-producing bacterial species, but were ineffective against the methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus is a bacterium responsible for several difficult-to-treat infections in humans. It is also called multidrug-resistant Staphylococcus aureus and oxacillin-resistant Staphylococcus aureus...

 (MRSA) strains that subsequently emerged.

Another development of the line of true penicillins was the antipseudomonal penicillins, such as carbenicillin
Carbenicillin
Carbenicillin is a bacteriolytic antibiotic belonging to the carboxypenicillin subgroup of the penicillins. It was discovered by scientists at Beecham and marketed as Pyopen. It has Gram-negative coverage which includes Pseudomonas aeruginosa but limited Gram-positive coverage...

, ticarcillin
Ticarcillin
Ticarcillin is a carboxypenicillin. It is almost invariably sold and used in combination with clavulanate as Timentin. Because it is a penicillin, it also falls within the larger class of beta-lactam antibiotics. Its main clinical use is as an injectable antibiotic for the treatment of...

, and piperacillin
Piperacillin
Piperacillin is an extended spectrum beta-lactam antibiotic of the ureidopenicillin class.It is normally used together with a beta-lactamase inhibitor such as tazobactam. The combination drug piperacillin/tazobactam is commercially available as e.g. Tazocin, Zosyn, Brodactam, Piptaz and as Trezora...

, useful for their activity against Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...

 bacteria. However, the usefulness of the β-lactam ring was such that related antibiotics, including the mecillinam
Mecillinam
Mecillinam or amdinocillin , trade name Coactin, is an extended-spectrum penicillin antibiotic that binds specifically to penicillin binding protein 2 , and is only considered to be active against Gram-negative bacteria. It is used primarily in the treatment of urinary tract infections, and has...

s, the carbapenem
Carbapenem
Carbapenems are a class of β-lactam antibiotics with a broad spectrum of antibacterial activity. They have a structure that renders them highly resistant to most β-lactamases...

s and, most important, the cephalosporin
Cephalosporin
The cephalosporins are a class of β-lactam antibiotics originally derived from Acremonium, which was previously known as "Cephalosporium".Together with cephamycins they constitute a subgroup of β-lactam antibiotics called cephems.-Medical use:...

s, still retain it at the center of their structures.

See also


  • β-Lactam antibiotic
    Beta-lactam antibiotic
    β-Lactam antibiotics are a broad class of antibiotics, consisting of all antibiotic agents that contains a β-lactam nucleus in its molecular structure. This includes penicillin derivatives , cephalosporins , monobactams, and carbapenems...

  • Drug allergy
    Drug allergy
    A drug allergy is an allergy to a drug, most commonly a medication. Medical attention should be sought immediately if an allergic reaction is suspected....

  • History of penicillin
  • Penicillinase

External links