Erythromycin

Structural formula
	Erythromycin A
General
Non-proprietary name	Erythromycin
other names	6- (4-Dimethylamino-3-hydroxy-6-methyl-oxan-2-yl) oxy-14-ethyl-7,12,13-trihydroxy-4- (5-hydroxy-4-methoxy-4,6- dimethyl-oxan-2-yl) -oxy-3,5,7,9,11,13-hexamethyl-1-oxacyclotetradecan-2,10-dione ( IUPAC ); Erythromycinum ( Latin );
Molecular formula	C 37 H 67 NO 13
Brief description	white to yellow, crystalline solid
External identifiers / databases
EC number	204-040-1
ECHA InfoCard	100.003.673
PubChem	12560
ChemSpider	12041
DrugBank	DB00199
Wikidata	Q213511
Drug information
ATC code	J01 FA01 ; D10 AF02 ; S01 AA17 ;
Drug class	Macrolide antibiotic
Mechanism of action	Inhibition of bacterial protein synthesis
properties
Molar mass	733.93 g · mol -1
density	1.209 g / cm 3
Melting point	138 ° C (hydrate); 190–193 ° C (anhydrous); 135-140 ° C ;
pK s value	8.6-8.8
solubility	very low ( decreases with increasing temperature ); 2.0 g / l at 20 ° C ;
Refractive index	1.535
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances danger
H and P phrases	H: 317-334
	P: 261-285
Toxicological data	9272 mg kg −1 ( LD 50 , rat , oral ) ; 4600 mg kg −1 ( LD 50 , rat , oral ) ; 426 mg kg −1 ( LD 50 , mouse , iv ) ; 2580 mg kg −1 ( LD 50 , mouse , oral ) ; 3018 mg kg −1 ( LD 50 , hamster , oral ) ;
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . Refractive index: Na-D line , 20 ° C

Erythromycin is a mixture of structurally very similar compounds that are formed by the bacterium Saccharopolyspora erythraea . Because of its antibiotic effects, erythromycin is used as a medicinal substance.

The main component is erythromycin A, up to 5% erythromycin B and a smaller amount erythromycin C also occur. Chemically, erythromycin is one of the glycosides , pharmacologically it is one of the macrolide antibiotics . Erythromycin is used to treat infections with gram-positive germs ( streptococci , staphylococci ), anaerobic germs ( propionibacteria , corynebacteria ) and mycoplasma .

history

In 1949 the Filipino scientist Abelardo Aguilar sent soil samples from the province of Iloilo to his employer, the pharmaceutical company Lilly . There a working group under James M. McGuire isolated erythromycin from culture filtrates as a metabolic product of Streptomyces erythreus (today Saccharopolyspora erythraea ). Marketed as Ilosone since 1952 , Lilly received US Patent 2,653,899 for this compound in 1953 . Other trade names were Erycinum ( Schering ) and Erythromycin ( Abbott ). The total synthesis of erythromycin was achieved by Robert B. Woodward and co-workers in 1981.

Mechanism of action

Erythromycin inhibits the translocation process during translation, which is catalyzed by the elongation factor EF-G. EF-G has the function of a GTPase , i.e. it causes GTP to break down into GDP + P _i . The energy released is used to detach the free tRNA molecules from the ribosome and thus enable it to move. A lack of the elongation factor prevents protein biosynthesis .

Erythromycin acts against gram-positive germs, against a few gram-negative germs ( Bordetella , Legionella , Chlamydia ) as well as against mycoplasma and some rickettsiae . It is a narrow-spectrum antibiotic.

Clinical information

application areas

The spectrum of activity of erythromycin is comparable to the spectrum of activity of some penicillins , which results in similar areas of application. Erythromycin can therefore be used if there are allergies to β-lactam antibiotics or if resistance prevents their use.

Oral therapy is indicated for by erythromycin-sensitive pathogens infectious diseases caused of the ear, nose and ear region ( ear infection , sinus infection ), deep airways ( bronchitis , pneumonia ), of the conjunctiva in erysipelas ( Erysipelas ), diphtheria , severe forms of Acne vulgaris and certain forms of urethritis. When (more effective) other antibiotics cannot be given, e.g. B. in penicillin allergy, erythromycin is also indicated for the treatment of inflammation of the pharyngitis or tonsils ( tonsillitis ), scarlet fever or syphilis .

If oral administration is not possible, erythromycin can be administered parenterally.

Erythromycin is used topically in particular in the treatment of inflammatory forms of acne .

Erythromycin can also be used for motility and emptying disorders of the stomach when the first-line drugs metoclopramide and domperidone do not improve. However, the use of erythromycin as a prokinetic takes place under the conditions of off-label use . Erythromycin binds to the motilin receptor even in subantibiotic doses and thus promotes gastrointestinal peristalsis, relaxes the pyloric muscles and coordinates the motor activities of the stomach and duodenum.

Interactions and side effects

Erythromycin is an inhibitor of the cytochrome P450 3A4 , 3A5 and 3A7. Thus, the biotransformation of drugs in which this enzyme is involved, e.g. B. Ciclosporin , Diazepam , Lidocaine , Warfarin u. v. a., impaired, which leads to the accumulation of active substances and to the intensification of main and side effects.

Erythromycin is well tolerated; the most common undesirable effects are mild gastrointestinal disorders. Erythromycin is a powerful prokinetic that speeds up gastric emptying. Anaphylactic reactions, tinnitus or mostly temporary hearing loss or deafness occur very rarely .

However, cardiac arrhythmias can also occur as a result of increasing the QTc time .

Chemical and pharmaceutical information

What the erythromycins have in common is a 14-membered lactone ring without double bonds (erythronolide structure). This is methyl-branched at every second C atom and is glycosidically linked at C-6 with the amino sugar desosamine and at C-4 with a neutral sugar (erythromycin A and B: cladinose , erythromycin C and D: mycarose ).

Erythromycin A is sparingly soluble in water and forms colorless to slightly yellowish crystals.

The erythromycins are stable when dry, but gradually decompose in solution even at room temperature. Degradation occurs rapidly when heated above 60 ° C and in acidic or alkaline solutions.

Structure of the erythromycins
Erythromycin	R ¹	R ²
A.	-OH	-CH ₃
B.	-H	-CH ₃
C.	-OH	-H

Pharmacokinetics

Erythromycin, micronized

Erythromycin is mainly excreted in the biliary with a half-life of 1.5 to 2.5 hours. Therefore administration is indicated every 6 hours.

Salts and esters

Erythromycin base is not acid stable, so that for the peroral treatment with either enteric-coated dosage forms need to be come or application but acid-resistant derivatives of erythromycin used in drug production: so are the esters of the hydroxy group at the C-2 'of the Desoxamins, erythromycin stearate and Erythromycinethyl succinate and Erythromycin estolate, the dodecyl sulfate salt of erythromycin propionate, used in tablets, capsules and suspensions. The esters are prodrugs because the free 2'-OH group of the amino sugar is important for the bond.

Water-soluble salts such as erythromycin lactobionate are used for the production of parenteral dosage forms.

Erythromycin as a free base is used in preparations to be used externally, for example in alcoholic solutions, gel , cream or ointment bases (e.g. for topical acne therapy ).

Other derivatives

Erythromycin is the lead substance in macrolide antibiotics. 7- O -methyl-erithromycin ( clarithromycin ) and erythromycin-9 - {( E ) - O - [(2-methoxyethoxy) methyl] oxime} ( roxithromycin ) are obtained from erythromycin by partial synthesis .

The ring-substituted azithromycin differs from erythromycin A in that the erythronolide structure is extended by a carbon atom between C-9 and C-10, the carbonyl function at C-10 is replaced by a methylamino group (azalide).

Clarithromycin , roxithromycin and azithromycin are also used as drugs.

biosynthesis

The enzyme complex

The erythromycin precursor is synthesized by a modular polyketide synthase. Such an enzyme has numerous active centers , organized in several modules, which build up the carbon structure as if on an assembly line. The enzyme deoxyerythronolide B synthase (DEBS), which is involved in the biosynthesis of erythromycin A in Saccharopolyspora erythraea , consists of 6 modules, a loading module and a release module (8 in total). There are 28 active centers in the large enzyme complex:

In the loading module , propionyl-CoA is loaded onto the DEBS enzyme with elimination of HS-CoA . Six more propionyl groups are added and modified over the six modules until a C15 chain is present. The substrate moves linearly through the modules, comparable to assembly line work. The release module cyclizes the chain to a fourteen -membered lactone heterocycle, 6-deoxyerythronolide B (6dEB). This lactone is released by the enzyme and modified to erythromycin A in just a few steps.

The individual active centers

The function of the active centers are briefly explained below. The reaction types are in brackets:

ACP anchors the substrate with the enzyme complex via a thioester .

AT transfers the substrate to the appropriate ACPs. ( Transesterification )

KS takes over the substrate from ACP and couples it with another propionyl group. ( Transesterification and ester condensation )

KR reduces a β-ketothioester to a β-hydroxythioester. ( Reduction )

DH eliminates water from a β-hydroxythioester and creates an α-β-unsaturated thioester. ( Elimination / dehydration )

ER hydrogenates the α-β-unsaturated thioester on the double bond . ( Hydrogenation )

TE cyclizes the substrate to the lactone. (Transesterification)

Provision and coupling of propionyl groups

The carbon backbone is made up only of propionyl groups. The cell starts with propionyl-CoA. All other propionyl groups are obtained from methyl-malonyl-CoA . The following scheme shows the coupling of two propionyl units. The numbers in the subscript of the enzymes refer to the module. 0 = loading module, 1 = module 1 (see diagram above).

In the loading module, AT _{0 transfers} propionyl from propionyl-CoA to ACP ₀ . Finally, propionyl is transferred to KS ₁ in module 1. In module 1, methyl-malonyl from methyl-malonyl-CoA is still transferred to ACP ₁ by AT ₁ . Methyl-malonyl-ACP ₁ is then decarboxylated to an enolate and can nucleophilically attack propionyl-S-KS ₁ . This reaction corresponds to a Claisen (thio) ester condensation .

Reaction path

The following scheme shows the entire reaction path from propionyl-CoA to 6-dEB and finally to erythromycin A. The provision of methyl-malonyl-S-ACP is no longer explicitly shown.

Trade names

Monopreparations: AknedermEry (D), Aknefug-EL (D), Aknemycin solution / ointment (D), Aknilox (CH), Erios (CH), Eryaknen (D, A, CH), Eryfluid (A), Erythrocin (A), Inderm (D), Infectomycin (D), Meromycin (A), Paediathrocin (D), Sanasepton (D), Stiemycine (D), numerous generics (D, A, CH)
Combination preparations: Aknemycin Emulsion / Plus / Ointment (D, A, CH), Isotrexin (D, A), Zineryt (D)
Veterinary medicine: Erythrocin vet., Erythrocin, Erythromycinthiocyanat, Erytrotil

literature

Red List - drug directory for Germany . Rote Liste Service ( Rote-liste.de [accessed on July 8, 2011] DocCheck password required).
European Pharmacopoeia Commission (Ed.): European Pharmacopoeia (Pharmacopoea Europaea, Ph.Eur.) .

Web links

Information at MedlinePlus (English)

Individual evidence

↑ ^a ^b ^c ^d ^e Erythromycin data sheet (PDF) from Calbiochem, accessed on December 7, 2015.
↑ ^a ^b Erythromycin at ChemSpider
↑ ^a ^b ^c ^d F. von Bruchhausen, S. Ebel, AW Frahm, E. Hackenthal: Hagers Handbook of Pharmaceutical Practice . Volume 8: fabrics E – O 5th edition. Birkhäuser, 1991, ISBN 978-3-540-52688-9 , p. 70.
↑ ^a ^b ^c ^d ^e ^f data sheet erythromycin, micronized by Caelo, as of November 27, 2018; accessed on December 19, 2019.
^ Theodor Dingermann (Ed.), Rudolf Hänsel (Ed.) And Ilse Zündorf (Ed.): Pharmaceutical Biology: Molecular Basics and Clinical Applications. Springer Verlag Berlin; 1st edition 2002; ISBN 3-540-42844-5 ; Pp. 316-317.
↑ Karl Wurm, AM Walter: Infectious Diseases. In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. Springer-Verlag, Berlin / Göttingen / Heidelberg 1955; 2nd edition ibid. 1961, pp. 9-223, here: p. 53 (isolated 1952).
↑ Patent US2653899 : Erythromycin, its salts, and method of preparation. Filed April 14, 1952 , published September 29, 1953 , Applicant: Eli Lilly and Company, Inventor: Robert L. Bunch, James M. McGuire. ‌
↑ RB Woodward et al .: Asymmetric Total Synthesis of Erythromycin. 1. Synthesis of an Erythronolide A Seco Acid Derivative via Asymmetric Induction. In: Journal of the American Chemical Society , 1981, 103, p. 3210.
↑ RB Woodward et al .: Asymmetric Total Synthesis of Erythromycin. 2. Synthesis of an Erythronolide A Lactone System. In: Journal of the American Chemical Society , 1981, 103, p. 3213.
↑ RB Woodward et al .: Asymmetric Total Synthesis of Erythromycin. 3. Total Synthesis of Erythromycin. In: Journal of the American Chemical Society , 1981, 103, p. 3215.
↑ Mutschler, drug effects, 9th edition, Wissenschaftliche Verlagsgesellschaft Stuttgart, 2008 ISBN 978-3-8047-1952-1
↑ WA. Ray et al .: Oral Erythromycin and the Risk of Sudden Death from Cardiac Causes. In: N. Engl. J. Med. , 2004, 351, 11, pp. 1089-1096. PMID 15356306 , free full text (PDF) (English).
^ Department of Medicine at Indiana University: P450 Drug Interaction Table .
↑ GR. Robertson et al .: Transgenic mouse models of human CYP3A4 gene regulation . In: Mol Pharmacol . , 2003, 64 (1), pp. 42-50. PMID 12815159 , free full text (PDF) (English).
↑ Torsten Kratz, Albert Diefenbacher: Psychopharmacotherapy in old age. Avoidance of drug interactions and polypharmacy. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f. (July 22) 2019, pp. 508-517, p. 512.
↑ H. Lüllmann, K. Mohr, L. Hein: Pharmakologie und Toxikologie , 16th edition Georg Thieme Verlag, Stuttgart, 2006.
^ Joan L. Slonczewski, John W. Foster: Microbiology . 2nd Edition. Springer-Verlag, Berlin Heidelberg 2012, ISBN 978-3-8274-2909-4 , p. 656 .
^ Donald Voet, Judith G. Voet, Charlotte W. Pratt: Textbook of Biochemistry . 3. Edition. Wiley-VCH, Weinheim 2019, ISBN 978-3-527-34286-0 , pp. 846 .
↑ Red List 2017 - drug directory for Germany (including EU approvals and certain medical devices) . Edition 57. Rote Liste Service, Frankfurt / Main 2017, ISBN 978-3-946057-10-9 , p. 613.

[merck-1] Erythromycin data sheet (PDF) from Calbiochem, accessed on December 7, 2015.

[Spider-2] Erythromycin at ChemSpider

[hager-3] F. von Bruchhausen, S. Ebel, AW Frahm, E. Hackenthal: Hagers Handbook of Pharmaceutical Practice . Volume 8: fabrics E – O 5th edition. Birkhäuser, 1991, ISBN 978-3-540-52688-9 , p. 70.

[Caelo-4] ↑ ^a ^b ^c ^d ^e ^f data sheet erythromycin, micronized by Caelo, as of November 27, 2018; accessed on December 19, 2019.

[5] Theodor Dingermann (Ed.), Rudolf Hänsel (Ed.) And Ilse Zündorf (Ed.): Pharmaceutical Biology: Molecular Basics and Clinical Applications. Springer Verlag Berlin; 1st edition 2002; ISBN 3-540-42844-5 ; Pp. 316-317.

[6] Karl Wurm, AM Walter: Infectious Diseases. In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. Springer-Verlag, Berlin / Göttingen / Heidelberg 1955; 2nd edition ibid. 1961, pp. 9-223, here: p. 53 (isolated 1952).

[7] Patent US2653899 : Erythromycin, its salts, and method of preparation. Filed April 14, 1952 , published September 29, 1953 , Applicant: Eli Lilly and Company, Inventor: Robert L. Bunch, James M. McGuire. ‌

[8] RB Woodward et al .: Asymmetric Total Synthesis of Erythromycin. 1. Synthesis of an Erythronolide A Seco Acid Derivative via Asymmetric Induction. In: Journal of the American Chemical Society , 1981, 103, p. 3210.

[9] RB Woodward et al .: Asymmetric Total Synthesis of Erythromycin. 2. Synthesis of an Erythronolide A Lactone System. In: Journal of the American Chemical Society , 1981, 103, p. 3213.

[10] RB Woodward et al .: Asymmetric Total Synthesis of Erythromycin. 3. Total Synthesis of Erythromycin. In: Journal of the American Chemical Society , 1981, 103, p. 3215.

[11] Mutschler, drug effects, 9th edition, Wissenschaftliche Verlagsgesellschaft Stuttgart, 2008 ISBN 978-3-8047-1952-1

[12] WA. Ray et al .: Oral Erythromycin and the Risk of Sudden Death from Cardiac Causes. In: N. Engl. J. Med. , 2004, 351, 11, pp. 1089-1096. PMID 15356306 , free full text (PDF) (English).

[13] Department of Medicine at Indiana University: P450 Drug Interaction Table .

[14] GR. Robertson et al .: Transgenic mouse models of human CYP3A4 gene regulation . In: Mol Pharmacol . , 2003, 64 (1), pp. 42-50. PMID 12815159 , free full text (PDF) (English).

[15] Torsten Kratz, Albert Diefenbacher: Psychopharmacotherapy in old age. Avoidance of drug interactions and polypharmacy. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f. (July 22) 2019, pp. 508-517, p. 512.

[16] H. Lüllmann, K. Mohr, L. Hein: Pharmakologie und Toxikologie , 16th edition Georg Thieme Verlag, Stuttgart, 2006.

[17] Joan L. Slonczewski, John W. Foster: Microbiology . 2nd Edition. Springer-Verlag, Berlin Heidelberg 2012, ISBN 978-3-8274-2909-4 , p. 656 .

[18] Donald Voet, Judith G. Voet, Charlotte W. Pratt: Textbook of Biochemistry . 3. Edition. Wiley-VCH, Weinheim 2019, ISBN 978-3-527-34286-0 , pp. 846 .

[Rote_Liste-19] Red List 2017 - drug directory for Germany (including EU approvals and certain medical devices) . Edition 57. Rote Liste Service, Frankfurt / Main 2017, ISBN 978-3-946057-10-9 , p. 613.