Natamycin, also known as pimaricin, is an

antifungal medication An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryp ...

used to treat

fungal infections Fungal infection, also known as mycosis, is disease caused by fungi. Different types are traditionally divided according to the part of the body affected; superficial, subcutaneous, and systemic. Superficial fungal infections include common ti ...

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. The human eye ...

conjunctiva The conjunctiva 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 goblet cells, stratified columnar epithel ...

, and

cornea The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical ...

. 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 b ...

Allergic reactions Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...

may occur. It is unclear if medical use during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...

is safe. It is in the

macrolide The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Ma ...

and

polyene In organic chemistry, polyenes are poly- unsaturated, organic compounds that contain at least three alternating double () and single () carbon–carbon bonds. These carbon–carbon double bonds interact in a process known as conjugation, result ...

families of medications. It results in fungal death by altering the

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

. 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 metabolic process that produces chemical changes in organic substrates through the action of enzymes. In biochemistry, it is narrowly defined as the extraction of energy from carbohydrates in the absence of oxygen. In food p ...

of certain types of the bacterium ''

Streptomyces ''Streptomyces'' is the largest genus of Actinomycetota and the type genus of the family Streptomycetaceae. Over 500 species of ''Streptomyces'' bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positiv ...

''.

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, Mic ...

'', ''

Cephalosporium ''Acremonium'' is a genus of fungi in the family Hypocreaceae. It used to be known as ''Cephalosporium''. Description ''Acremonium'' species are usually slow-growing and are initially compact and moist. Their hyphae are fine and hyaline, and pro ...

'', ''

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 soil mi ...

'', and ''

Penicillium ''Penicillium'' () is a genus of ascomycetous 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 the genus produce pe ...

''. It is applied topically as a cream, in eye drops, or (for oral infections) in a

lozenge Lozenge or losange may refer to: *Lozenge (shape), a type of rhombus *Throat lozenge, a tablet intended to be dissolved slowly in the mouth to suppress throat ailments *Lozenge (heraldry), a diamond-shaped object that can be placed on the field of ...

. 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 also prescribed to treat yeast infections and

oral thrush Oral candidiasis, also known as oral thrush among other names, is candidiasis that occurs in the mouth. That is, oral candidiasis is a mycosis (yeast/fungal infection) of ''Candida'' species on the mucous membranes of the mouth. ''Candida albica ...

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 is a high-concentration solution of salt (NaCl) in water (H2O). In diverse contexts, ''brine'' may refer to the salt solutions ranging from about 3.5% (a typical concentration of seawater, on the lower end of that of solutions used for ...

) 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 mechanisms ...

such as

cellulose Cellulose is an organic compound with the formula , a polysaccharide consisting of a linear chain of several hundred to many thousands of β(1→4) linked D-glucose units. Cellulose is an important structural component of the primary cell wa ...

) sprinkled on or mixed into the product. 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. Also, 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 isol ...

. As a

food additive Food additives are substances added to food to preserve Taste, flavor or enhance taste, appearance, or other sensory qualities. Some additives have been used for centuries as part of an effort to preserve food, for example vinegar (pickling), sal ...

, it has

E number E numbers ("E" stands for "Europe") 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. 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 The Scientific Committee on Food (SCF), established in 1974, was the main committee providing the European Commission with scientific advice on food safety. "Scientific Committee on Food - FOOD STANDARDS AGENCY" (overview), Gov.uk, F ...

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.Scientific Opinion on the use of natamycin (E 235) as a food additive
/ref>

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 2 years caused no detectable differences in survival rate, growth, or incidence of tumors. 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, ...

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.Mattia, A. et al. Safety evaluation of certain food additives and contaminants: natamicin (pimaricin). WHO Food Additives Series #48.
/ref> 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 sterol 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 ergosterol, t ...

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 ''

'' 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 In microbiology, the minimum inhibitory concentration (MIC) is the lowest concentration of a chemical, usually a drug, which prevents visible growth of a bacterium or bacteria. MIC depends on the microorganism, the affected human being (in vivo only ...

is less than 10 ppm for most molds.

Biochemistry

Natamycin is produced as a

secondary metabolite Secondary metabolites, also called specialised metabolites, toxins, secondary products, or natural products, are organic compounds produced by any lifeform, e.g. bacteria, fungi, animals, or plants, which are not directly involved in the norma ...

by some ''Streptomyces'' species: '' S. natalensis'', '' S. lydicus'', '' S. chattanoogensis'' and '' S. gilvosporeus''. Structurally, its core is a

containing a

segment, with

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyli ...

and mycosamine groups attached. As with other

polyene antimycotic Polyene antimycotics, sometimes referred to as polyene antibiotics, are a class of antimicrobial polyene compounds that target fungi. These polyene antimycotics are typically obtained from some species of ''Streptomyces'' bacteria. Previously, ...

s, the

biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecul ...

begins with a series of

polyketide synthase Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

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."Pimaricin, a new antifungal antibiotic" in Antibiotics Annual in 1957. Natamycin VGP (http://www.natamycinvgp.com/the-origins-of-natamycin/#prettyPhoto) It was originally named ''pimaricin'' to honor

Pietermaritzburg Pietermaritzburg (; Zulu: umGungundlovu) is the capital and second-largest city in the province of KwaZulu-Natal, South Africa. It was founded in 1838 and is currently governed by the Msunduzi Local Municipality. Its Zulu name umGungundlovu ...

, where ''Streptomyces natalensis'' was acquired. Pimaricin was later renamed after the

World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...

(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 Whole Foods Market IP, Inc., a subsidiary of Amazon, is an upscale American multinational supermarket chain headquartered in Austin, Texas, which sells products free from hydrogenated fats and artificial colors, flavors, and preservatives. A US ...

' "Unacceptable Ingredients for Food" list.Unacceptable Ingredients for Food (http://www.wholefoodsmarket.com/about-our-products/quality-standards/food-ingredient)

References

External links

Natacyn Side Effects Center
* {{portal bar, Medicine Antifungals Preservatives Macrolides Polyenes Epoxides World Health Organization essential medicines Wikipedia medicine articles ready to translate E-number additives