Natamycin
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Natamycin, also known as pimaricin, is an antifungal medication used to treat fungal infections around the eye. This includes infections of the
eyelids An eyelid ( ) is a thin fold of skin that covers and protects an eye. The levator palpebrae superioris muscle retracts the eyelid, exposing the cornea to the outside, giving vision. This can be either voluntarily or involuntarily. "Palpebral" ...
,
conjunctiva In the anatomy of the eye, the conjunctiva (: conjunctivae) is a thin mucous membrane that lines the inside of the eyelids and covers the sclera (the white of the eye). It is composed of non-keratinized, stratified squamous epithelium with gobl ...
, and
cornea The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...
. It is used as eyedrops. Natamycin is also used in the food industry as a
preservative A preservative is a substance or a chemical that is added to products such as food products, beverages, pharmaceutical drugs, paints, biological samples, cosmetics, wood, and many other products to prevent decomposition by microbial growth or ...
.
Allergic reactions Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, alle ...
may occur. It is unclear if medical use during
pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
or
breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...
is safe. It is in the
macrolide Macrolides are a class of mostly natural products with a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. Macrolides belong to the polyketide class of natural products. ...
and
polyene In organic chemistry, polyenes are polyunsaturated organic compounds that contain multiple carbon–carbon double bonds (). Some sources consider dienes to be polyenes, whereas others require polyenes to contain at least three carbon–carbon d ...
families of medications. It results in fungal death by altering the
cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
. Natamycin was discovered in 1955 and approved for medical use in the United States in 1978. It is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...
. It is produced by
fermentation Fermentation is a type of anaerobic metabolism which harnesses the redox potential of the reactants to make adenosine triphosphate (ATP) and organic end products. Organic molecules, such as glucose or other sugars, are catabolized and reduce ...
of certain types of the bacterium ''
Streptomyces ''Streptomyces'', from στρεπτός (''streptós''), meaning "twisted", and μύκης (''múkés''), meaning "fungus", is the largest genus of Actinomycetota, and the type genus of the family Streptomycetaceae. Over 700 species of ''St ...
''.


Uses


Medical

Natamycin is used to treat fungal infections, including '' Candida'', ''
Aspergillus ' () is a genus consisting of several hundred mold species found in various climates worldwide. ''Aspergillus'' was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli. Viewing the fungi under a microscope, Miche ...
'', '' Cephalosporium'', ''
Fusarium ''Fusarium'' (; ) is a large genus of filamentous fungi, part of a group often referred to as hyphomycetes, widely distributed in soil and associated with plants. Most species are harmless saprobes, and are relatively abundant members of the s ...
'', and ''
Penicillium ''Penicillium'' () is a genus of Ascomycota, ascomycetous fungus, fungi that is part of the mycobiome of many species and is of major importance in the natural environment, in food spoilage, and in food and drug production. Some members of th ...
''. It is applied topically as a cream, in eye drops, or (for oral infections) in a lozenge. Natamycin shows negligible absorption into the body when administered in these ways. When taken orally, little or none is absorbed from the gastrointestinal tract, making it inappropriate for systemic infections. Natamycin lozenges are used by veterinarians for oral thrush.


Food

Natamycin has been used for decades in the food industry as a hurdle to fungal outgrowth in dairy products and other foods. Potential advantages for the usage of natamycin might include the replacement of traditional chemical preservatives, a neutral flavor impact, and less dependence on pH for efficacy, as is common with chemical preservatives. It can be applied in a variety of ways: as an aqueous suspension (such as mixed into a
brine Brine (or briny water) is a high-concentration solution of salt (typically sodium chloride or calcium chloride) in water. In diverse contexts, ''brine'' may refer to the salt solutions ranging from about 3.5% (a typical concentration of seawat ...
) sprayed on the product or into which the product is dipped, or in powdered form (along with an
anticaking agent An anticaking agent is an additive placed in powdered or granulated materials, such as table salt or confectioneries, to prevent the formation of lumps ( caking) and for easing packaging, transport, flowability, and consumption. Caking mechanism ...
such as
cellulose Cellulose is an organic compound with the chemical formula, formula , a polysaccharide consisting of a linear chain of several hundred to many thousands of glycosidic bond, β(1→4) linked glucose, D-glucose units. Cellulose is an important s ...
) sprinkled on or mixed into the product. Natamycin is approved for various dairy applications in the United States. More specifically, natamycin is commonly used in products such as cream cheeses, cottage cheese, sour cream, yogurt, shredded cheeses, cheese slices, and packaged salad mixes. One of the reasons for food producers to use natamycin is to replace the artificial preservative
sorbic acid Sorbic acid, or 2,4-hexadienoic acid, is a natural organic compound used as a food preservative. It has the chemical formula and the structure . It is a colourless solid that is slightly soluble in water and sublimes readily. It was first iso ...
. Natamycin is also known to diffuse slower and lesser into cheese when compared to sorbate, which could otherwise cause undesirable changes to the flavor. As a
food additive Food additives are substances added to food to preserve flavor or enhance taste, appearance, or other sensory qualities. Some additives, such as vinegar ( pickling), salt ( salting), smoke ( smoking) and sugar ( crystallization), have been used f ...
, it has
E number E numbers, short for Europe numbers, are codes for substances used as food additives, including those found naturally in many foods, such as vitamin C, for use within the European Union (EU) and European Free Trade Association (EFTA). Commonly ...
E235. Throughout the European Union, it is approved only as a surface preservative for certain cheese and dried sausage products. It must not be detectable 5 mm below the rind. While natamycin is approved in different applications at different levels in the world, it is approved in over 150 countries worldwide. While not currently approved for use on meats in the United States, some countries allow natamycin to be applied to the surface of dry and fermented sausages to prevent mold growth on the casing. Sausages that contain cheese, even in countries that don't allow its use on meats, may contain and list natamycin as an ingredient. The
European Food Safety Authority The European Food Safety Authority (EFSA) is the agency of the European Union (EU) that provides independent scientific advice and communicates on existing and emerging risks associated with the food chain. EFSA was established in February 2002 ...
(EFSA) panel took over the responsibilities of providing scientific food safety advice to the EU from the Scientific Committee on Food in 2002. In 2009, the EFSA considered the proposed use levels of natamycin are safe if it is used for the surface treatment for these cheese and sausage types.


Safety

Natamycin does not have
acute toxicity Acute toxicity describes the adverse effects of a substance that result either from a single exposure or from multiple exposures in a short period of time (usually less than 24 hours). To be described as ''acute'' toxicity, the adverse effect ...
. In animal studies, the lowest found was 2.5–4.5 g/kg. In rats, the LD50 is ≥2300 mg/kg, and doses of 500 mg/kg/day over two years caused no detectable differences in survival rate, growth, or incidence of
tumors A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
. The
metabolites In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
of natamycin also lack toxicity. The breakdown products of natamycin under various storage conditions may have a lower LD50 than natamycin, but in all cases, the numbers are quite high. In humans, a dose of 500 mg/kg/day repeated over multiple days caused nausea, vomiting, and diarrhea. No evidence shows natamycin, at either pharmacological levels or levels encountered as a food additive, can harm normal intestinal flora, but definitive research may not be available. However, some people are allergic to natamycin. The EFSA has concluded that the use of natamycin as a food additive has no relevant risk for the development of resistant fungi.


Mechanism of action

Natamycin inhibits the growth of fungi by specifically binding to
ergosterol Ergosterol (ergosta-5,7,22-trien-3β-ol) is a mycosterol found in cell membranes of fungi and protozoa, serving many of the same functions that cholesterol serves in animal cells. Because many fungi and protozoa cannot survive without ergostero ...
present in fungal cell membranes. Natamycin inhibits amino acid and glucose transport proteins leading to a loss of nutrient transport across the plasma membrane. While this binding is reversible, ergosterol binding acts as a universal mechanism of fungal inhibition, allowing natamycin to act on diverse fungal pathogens from ''
Saccharomyces ''Saccharomyces'' is a genus of fungi that includes many species of yeasts. ''Saccharomyces'' is from Greek σάκχαρον (sugar) and μύκης (fungus) and means ''sugar fungus''. Many members of this genus are considered very important in f ...
'' yeast to ''
Aspergillus ' () is a genus consisting of several hundred mold species found in various climates worldwide. ''Aspergillus'' was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli. Viewing the fungi under a microscope, Miche ...
'' moulds. Natamycin is unique amongst related antifungals specifically because it does not directly cause membrane permeabilization. Structurally-related antibiotics with similar binding properties are thought to produce hydrophilic channels that allow leakage of potassium and sodium ions from the cell. Natamycin has very low solubility in water; however, natamycin is effective at very low levels. Its minimum inhibitory concentration is less than 10  ppm for most molds.


Biochemistry

Natamycin is produced as a
secondary metabolite Secondary metabolites, also called ''specialised metabolites'', ''secondary products'', or ''natural products'', are organic compounds produced by any lifeform, e.g. bacteria, archaea, fungi, animals, or plants, which are not directly involved ...
by some ''Streptomyces'' species: '' S. natalensis'', '' S. lydicus'', '' S. chattanoogensis'' and '' S. gilvosporeus''. Structurally, its core is a
macrolide Macrolides are a class of mostly natural products with a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. Macrolides belong to the polyketide class of natural products. ...
containing a
polyene In organic chemistry, polyenes are polyunsaturated organic compounds that contain multiple carbon–carbon double bonds (). Some sources consider dienes to be polyenes, whereas others require polyenes to contain at least three carbon–carbon d ...
segment, with
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
and mycosamine groups attached. As with other polyene antimycotics, the
biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...
begins with a series of polyketide synthase modules, followed by additional enzymatic processes for oxidation and attachment of the substituents. Natamycin is produced on an industrial scale by fermentation of various ''Streptomyces'' strains, including ''S. chattanoogensis'' L10.


History

Natamycin was first isolated in 1955 from fermentation broth of a ''Streptomyces natalensis'' cell culture. It was originally named ''pimaricin'' to honor
Pietermaritzburg Pietermaritzburg (; ) is the capital and second-largest city in the province of KwaZulu-Natal, South Africa after Durban. It was named in 1838 and is currently governed by the Msunduzi Local Municipality. The town was named in Zulu after King ...
, where ''Streptomyces natalensis'' was acquired. Pimaricin was later renamed after the
World Health Organization The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...
(WHO) mandated that antibiotics produced by ''Streptomyces'' end in –mycin. The name ''natamycin'' was chosen in reference to the ''natalensis'' species name.


Society and culture

Natamycin appears on Whole Foods' "Unacceptable Ingredients for Food" list.


References

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