Natamycin

Last updated

Natamycin
Natamycin.svg
Natamycin ball-and-stick.png
Clinical data
Trade names Natacyn, others
AHFS/Drugs.com Monograph
Routes of
administration
Eye drops [1]
ATC code
Identifiers
  • (1R,3S,5R,7R,8E,12R,14E,16E,18E,20E,22R,24S,25R,26S)-22-[(3-amino-3,6-dideoxy-D-mannopyranosyl)oxy]-1,3,26-trihydroxy-12-methyl-10-oxo-6,11,28-trioxatricyclo[22.3.1.05,7]octacosa-8,14,16,18,20-pentaene-25-carboxylic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
E number E235 (preservatives) OOjs UI icon edit-ltr-progressive.svg
CompTox Dashboard (EPA)
ECHA InfoCard 100.028.803 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C33H47NO13
Molar mass 665.733 g·mol−1
3D model (JSmol)
Density 1.35 g/ml g/cm3
Melting point Darkens at ±200 °C with vigorous decomposition at 280-300 °C
Solubility in water 0.39 mg/ml
  • OC(=O)[C@@H]3[C@@H](O)C[C@@]2(O)C[C@@H](O)C[C@H]4O[C@@H]4/C=C/C(=O)O[C@H](C)C\C=C\C=C\C=C\C=C\[C@H](O[C@@H]1O[C@H](C)[C@@H](O)[C@H](N)[C@@H]1O)C[C@@H]3O2
  • InChI=1S/C33H47NO13/c1-18-10-8-6-4-3-5-7-9-11-21(45-32-30(39)28(34)29(38)19(2)44-32)15-25-27(31(40)41)22(36)17-33(42,47-25)16-20(35)14-24-23(46-24)12-13-26(37)43-18/h3-9,11-13,18-25,27-30,32,35-36,38-39,42H,10,14-17,34H2,1-2H3,(H,40,41)/b4-3+,7-5+,8-6+,11-9+,13-12+/t18-,19-,20+,21+,22+,23-,24-,25+,27-,28+,29-,30+,32+,33-/m1/s1
     Yes check.svgY
  • Key:NCXMLFZGDNKEPB-FFPOYIOWSA-N

Natamycin, also known as pimaricin, is an antifungal medication used to treat fungal infections around the eye. [1] [2] This includes infections of the eyelids, conjunctiva, and cornea. [1] It is used as eyedrops. [1] Natamycin is also used in the food industry as a preservative. [2]

Contents

Allergic reactions may occur. [1] It is unclear if medical use during pregnancy or breastfeeding is safe. [1] It is in the macrolide and polyene families of medications. [1] It results in fungal death by altering the cell membrane. [1]

Natamycin was discovered in 1955 and approved for medical use in the United States in 1978. [1] [2] It is on the World Health Organization's List of Essential Medicines. [3] It is produced by fermentation of certain types of the bacterium Streptomyces . [1] [4]

Uses

Medical

Natamycin is used to treat fungal infections, including Candida , Aspergillus , Cephalosporium , Fusarium , and Penicillium . 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. [5] Natamycin lozenges are also prescribed to treat yeast infections and oral thrush. [6]

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) sprayed on the product or into which the product is dipped, or in powdered form (along with an anticaking agent such as cellulose) sprinkled on or mixed into the product.[ citation needed ]

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. [7] Natamycin is also known to diffuse slower and lesser into cheese when compared to sorbate, which could otherwise cause undesirable changes to the flavor. [8]

As a food additive, it has E number 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. [9]

The European Food Safety Authority (EFSA) panel took over the responsibilities of providing scientific food safety advice to the EU from the Scientific Committee on Food in 2002. [10] 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. [11]

Safety

Natamycin does not have acute toxicity. In animal studies, the lowest LD50 found was 2.5-4.5 g/kg. [12] 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 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. [13]

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. [13] However, some people are allergic to natamycin. [14]

The EFSA has concluded that the use of natamycin as a food additive has no relevant risk for the development of resistant fungi. [11]

Mechanism of action

Natamycin inhibits the growth of fungi by specifically binding to ergosterol 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 yeast to Aspergillus moulds. Natamycin is unique amongst related antifungals specifically because it does not directly cause membrane permeabilization. [15] [16] [17] Structurally-related antibiotics with similar binding properties are thought to produce hydrophilic channels that allow leakage of potassium and sodium ions from the cell. [18]

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.[ citation needed ]

Biochemistry

Natamycin is produced as a secondary metabolite by some Streptomyces species: S. natalensis , S. lydicus , S. chattanoogensis and S. gilvosporeus . [4] Structurally, its core is a macrolide containing a polyene segment, with carboxylic acid and mycosamine groups attached. As with other polyene antimycotics, the biosynthesis begins with a series of polyketide synthase modules, followed by additional enzymatic processes for oxidation and attachment of the substituents. [19]

Natamycin is produced on an industrial scale by fermentation of various Streptomyces strains, including S. chattanoogensis L10. [19]

History

Natamycin was first isolated in 1955 from fermentation broth of a Streptomyces natalensis cell culture. [20] It was originally named pimaricin to honor Pietermaritzburg, where Streptomyces natalensis was acquired. Pimaricin was later renamed after the World Health Organization (WHO) mandated that antibiotics produced by Streptomyces end in –mycin. The name natamycin was chosen in reference to the natalensis species name. [20]

Society and culture

Natamycin appears on Whole Foods' "Unacceptable Ingredients for Food" list. [21]

Related Research Articles

<span class="mw-page-title-main">Nisin</span> Chemical compound

Nisin is a polycyclic antibacterial peptide produced by the bacterium Lactococcus lactis that is used as a food preservative. It has 34 amino acid residues, including the uncommon amino acids lanthionine (Lan), methyllanthionine (MeLan), didehydroalanine (Dha), and didehydroaminobutyric acid (Dhb). These unusual amino acids are introduced by posttranslational modification of the precursor peptide. In these reactions a ribosomally synthesized 57-mer is converted to the final peptide. The unsaturated amino acids originate from serine and threonine, and the enzyme-catalysed addition of cysteine residues to the didehydro amino acids result in the multiple (5) thioether bridges.

<span class="mw-page-title-main">Antifungal</span> Pharmaceutical fungicide or fungistatic used to treat and prevent mycosis

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 cryptococcal meningitis, and others. Such drugs are usually obtained by a doctor's prescription, but a few are available over the counter (OTC). The evolution of antifungal resistance is a growing threat to health globally.

<span class="mw-page-title-main">Xanthan gum</span> Polysaccharide gum used as a food additive and thickener

Xanthan gum is a polysaccharide with many industrial uses, including as a common food additive. It is an effective thickening agent and stabilizer that prevents ingredients from separating. It can be produced from simple sugars by fermentation and derives its name from the species of bacteria used, Xanthomonas campestris.

<span class="mw-page-title-main">Nystatin</span> Antifungal medication

Nystatin, sold under the brand name Mycostatin among others, is an antifungal medication. It is used to treat Candida infections of the skin including diaper rash, thrush, esophageal candidiasis, and vaginal yeast infections. It may also be used to prevent candidiasis in those who are at high risk. Nystatin may be used by mouth, in the vagina, or applied to the skin.

<span class="mw-page-title-main">Amphotericin B</span> Antifungal and antiparasitaric chemical compound

Amphotericin B is an antifungal medication used for serious fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, and cryptococcosis. For certain infections it is given with flucytosine. It is typically given intravenously.

An antimicrobial is an agent that kills microorganisms (microbicide) or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria, and antifungals are used against fungi. They can also be classified according to their function. The use of antimicrobial medicines to treat infection is known as antimicrobial chemotherapy, while the use of antimicrobial medicines to prevent infection is known as antimicrobial prophylaxis.

<span class="mw-page-title-main">Ionophore</span> Chemical entity that reversibly binds ions

In chemistry, an ionophore is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the cell membrane. Ionophores catalyze ion transport across hydrophobic membranes, such as liquid polymeric membranes or lipid bilayers found in the living cells or synthetic vesicles (liposomes). Structurally, an ionophore contains a hydrophilic center and a hydrophobic portion that interacts with the membrane.

<span class="mw-page-title-main">Tiabendazole</span> Chemical compound

Tiabendazole, also known as thiabendazole or TBZ and the trade names Mintezol, Tresaderm, and Arbotect, is a preservative, an antifungal agent, and an antiparasitic agent.

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, polyenes were thought to bind to ergosterol in the fungal cell membrane and thus weakening it and causing leakage of K+ and Na+ ions, which could contribute to fungal cell death. However, more detailed studies of polyene molecular properties have challenged this model suggesting that polyenes instead bind and extract ergosterol directly from the cellular membrane thus disrupting the many cellular functions ergosterols perform. Amphotericin B, nystatin, and natamycin are examples of polyene antimycotics. They are a subgroup of macrolides.

<span class="mw-page-title-main">Echinocandin</span> Group of chemical compounds

Echinocandins are a class of antifungal drugs that inhibit the synthesis of β-glucan in the fungal cell wall via noncompetitive inhibition of the enzyme 1,3-β glucan synthase. The class has been termed the "penicillin of antifungals," along with the related papulacandins, as their mechanism of action resembles that of penicillin in bacteria. β-glucans are carbohydrate polymers that are cross-linked with other fungal cell wall components, the fungal equivalent to bacterial peptidoglycan. Caspofungin, micafungin, and anidulafungin are semisynthetic echinocandin derivatives with limited clinical use due to their solubility, antifungal spectrum, and pharmacokinetic properties.

<span class="mw-page-title-main">Hamycin</span> Group of chemical compounds

Hamycin is a pair polyene antimycotic organic compounds described in India. It is a heptaene antifungal compound rather similar in chemical structure to amphotericin B except that it has an additional aromatic group bonded to the molecule. When pure, hamycin is a yellow, powdered solid. There are two versions of hamycin with very similar chemical structures: hamycin A and hamycin B.

<span class="mw-page-title-main">Sterol 14-demethylase</span> Class of enzymes

In enzymology, a sterol 14-demethylase (EC 1.14.13.70) is an enzyme of the cytochrome P450 (CYP) superfamily. It is any member of the CYP51 family. It catalyzes a chemical reaction such as:

<span class="mw-page-title-main">Hachimycin</span> Chemical compound

Hachimycin, also known as trichomycin, is a polyene macrolide antibiotic, antiprotozoal, and antifungal derived from streptomyces. It was first described in 1950, and in most research cases have been used for gynecological infections.

A lipopeptide is a molecule consisting of a lipid connected to a peptide. They are able to self-assemble into different structures. Many bacteria produce these molecules as a part of their metabolism, especially those of the genus Bacillus, Pseudomonas and Streptomyces. Certain lipopeptides are used as antibiotics. Due to the structural and molecular properties such as the fatty acid chain, it poses the effect of weakening the cell function or destroying the cell. Other lipopeptides are toll-like receptor agonists. Certain lipopeptides can have strong antifungal and hemolytic activities. It has been demonstrated that their activity is generally linked to interactions with the plasma membrane, and sterol components of the plasma membrane could play a major role in this interaction. It is a general trend that adding a lipid group of a certain length to a lipopeptide will increase its bactericidal activity. Lipopeptides with a higher amount of carbon atoms, for example 14 or 16, in its lipid tail will typically have antibacterial activity as well as anti-fungal activity. Therefore, an increase in the alkyl chain can make lipopeptides soluble in water. As well, it opens the cell membrane of the bacteria, so antimicrobial activity can take place.

<span class="mw-page-title-main">Polylysine</span> Chemical compound

Polylysine refers to several types of lysine homopolymers, which may differ from each other in terms of stereochemistry and link position (α/ε). Of these types, only ε-poly-L-lysine is produced naturally.

<span class="mw-page-title-main">Clavam</span> Class of antibiotics

Clavams are a class of antibiotics. This antibiotic is derived from Streptomyces clavuligerus NRRL 3585. Clavam is produced to form a new β-lactam antibiotic. This class is divided into the clavulanic acid class and the 5S clavams class. Both groups are the outcomes of the fermentation process produced by Streptomyces spp. Clavulanic acid is a broad-spectrum antibiotic and 5S clavams may have anti-fungal properties. They are similar to penams, but with an oxygen substituted for the sulfur. Thus, they are also known as oxapenams.

<i>Streptomyces natalensis</i> Species of bacterium

Streptomyces natalensis is a bacterial species in the genus Streptomyces.

Streptomyces isolates have yielded the majority of human, animal, and agricultural antibiotics, as well as a number of fundamental chemotherapy medicines. Streptomyces is the largest antibiotic-producing genus of Actinomycetota, producing chemotherapy, antibacterial, antifungal, antiparasitic drugs, and immunosuppressants. Streptomyces isolates are typically initiated with the aerial hyphal formation from the mycelium.

Streptomyces lydicus is a bacterium species from the genus of Streptomyces which has been isolated from soil in the United States. Streptomyces lydicus produces actithiazic acid, natamycin, lydimycin, streptolydigin, and 1-deoxygalactonojirimycin. Streptomyces lydicus can be used as an agent against fungal plant pathogens like Fusarium, Pythium, Phytophthora, Rhizoctonia and Verticillum.

Topical antifungaldrugs are used to treat fungal infections on the skin, scalp, nails, vagina or inside the mouth. These medications come as creams, gels, lotions, ointments, powders, shampoos, tinctures and sprays. Most antifungal drugs induce fungal cell death by destroying the cell wall of the fungus. These drugs inhibit the production of ergosterol, which is a fundamental component of the fungal cell membrane and wall.

References

  1. 1 2 3 4 5 6 7 8 9 10 "Natamycin". The American Society of Health-System Pharmacists. Retrieved 8 December 2017.
  2. 1 2 3 Davidson PM, Juneja VK, Branen J (2001). "Antimicrobial Agents". In Branen AL, Davidson PM, Salminen S, Thorngate J (eds.). Food Additives. CRC Press. pp. 599–600. ISBN   9780824741709.
  3. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  4. 1 2 Aparicio JF, Barreales EG, Payero TD, Vicente CM, de Pedro A, Santos-Aberturas J (January 2016). "Biotechnological production and application of the antibiotic pimaricin: biosynthesis and its regulation". Applied Microbiology and Biotechnology. 100 (1): 61–78. doi:10.1007/s00253-015-7077-0. PMC   4700089 . PMID   26512010.
  5. Brayfield A (2014). Martindale: The Complete Drug Reference (38th ed.). London: Pharmaceutical press. ISBN   978-0-85711-139-5.
  6. "Topical Antifungal Drugs: Natamycin". Virginia-Maryland Regional College of Veterinary Medicine. Archived from the original on 7 April 2017.)
  7. "Kraft Singles Ditch Artificial Preservatives". NBC News . 11 February 2014. Archived from the original on 8 October 2022.
  8. Youssef, A.M.; Assem, F.M.; El-Sayed, S.M.; Salama, H.; Abd El-Salam, M.H. (2017). "Utilization of Edible Films and Coatings as Packaging Materials for Preservation of Cheeses". J Package Technol Res. 1 (2): 87–99. doi:10.1007/s41783-017-0012-3. S2CID   257086547.
  9. "Regulatory and Approval Information". Natamycin.com.
  10. "Safety and regulation: the formal process for analyzing the test data on food additives". understandingfoodadditives.org. Archived from the original on 7 January 2014.
  11. 1 2 EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) (December 2009). "Scientific Opinion on the use of natamycin (E 235) as a food additive". EFSA Journal. 7 (12): 1412. doi: 10.2903/j.efsa.2009.1412 .
  12. Oostendorp JG (1981). "Natamysin(R)". Antonie van Leeuwenhoek. 47 (2): 170–171. doi:10.1007/bf02342201. S2CID   264007289.
  13. 1 2 Mattia A, Dr Cerniglia C, Baines J. Safety evaluation of certain food additives and contaminants: natamicin (pimaricin). WHO Food Additives Series #48 (Report). International Programme on Chemical Safety (IPCS).
  14. "Natamycin". RxList.
  15. te Welscher YM, ten Napel HH, Balagué MM, Souza CM, Riezman H, de Kruijff B, Breukink E (March 2008). "Natamycin blocks fungal growth by binding specifically to ergosterol without permeabilizing the membrane". The Journal of Biological Chemistry. 283 (10): 6393–6401. doi: 10.1074/jbc.M707821200 . PMID   18165687.
  16. Van Leeuwen MR, Golovina EA, Dijksterhuis J (June 2009). "The polyene antimycotics nystatin and filipin disrupt the plasma membrane, whereas natamycin inhibits endocytosis in germinating conidia of Penicillium discolor". Journal of Applied Microbiology. 106 (6): 1908–1918. doi:10.1111/j.1365-2672.2009.04165.x. PMID   19228256. S2CID   2873514.
  17. te Welscher YM, van Leeuwen MR, de Kruijff B, Dijksterhuis J, Breukink E (July 2012). "Polyene antibiotic that inhibits membrane transport proteins". Proceedings of the National Academy of Sciences of the United States of America. 109 (28): 11156–11159. Bibcode:2012PNAS..10911156T. doi: 10.1073/pnas.1203375109 . PMC   3396478 . PMID   22733749.
  18. Nedal A, Sletta H, Brautaset T, Borgos SE, Sekurova ON, Ellingsen TE, Zotchev SB (November 2007). "Analysis of the mycosamine biosynthesis and attachment genes in the nystatin biosynthetic gene cluster of Streptomyces noursei ATCC 11455". Applied and Environmental Microbiology. 73 (22): 7400–7407. Bibcode:2007ApEnM..73.7400N. doi:10.1128/AEM.01122-07. PMC   2168226 . PMID   17905880.
  19. 1 2 Liu SP, Yuan PH, Wang YY, Liu XF, Zhou ZX, Bu QT, et al. (April 2015). "Generation of the natamycin analogs by gene engineering of natamycin biosynthetic genes in Streptomyces chattanoogensis L10". Microbiological Research. 173: 25–33. doi: 10.1016/j.micres.2015.01.013 . PMID   25801968.
  20. 1 2 "The origins of natamycin". Archived from the original on 16 July 2014. Natamycin was isolated for the first time in 1955 in the Gist-brocades research laboratories, from the fermentation broth of a culture of Streptomyces natalensis.
  21. "Unacceptable Ingredients for Food". Whole Foods Market IP. L.P. Archived from the original on 2 January 2018.