Macrolide antibiotics

3.6 Macrolides

Macrolide antibiotics are typically characterized by macrocyclic lactones having a ring-size ranging between 12-16 atoms and also possess inherent extensive branching through the methyl substituents. However, the macrolactone ring essentially bears a glycosidal linkage to either one or several sugar functions. Exhaustive biosynthetic studies have revealed that the genesis and formation of macrocyclic lactone due to the condensation of either acetate and/or propionate units, evidently via malonyl-CoA and 2-methylmalonyl-CoA. Interestingly, the methyl substituents present on the macrolactone ring seem to be contributed exclusively as the residual from incorporation of propionate units instead of the so called terminal biological methylation. It has been established beyond any reasonable doubt that two or even more ‘sugar units’ are attached through the glycoside linkages. Further, these sugars are found to be somewhat unusual 6-deoxy structures normally restricted to this particular class of compounds i.e., macrolides.

The four ‘sugar components’ present often in macrolides are, namely: L-cladinose; L-mycarose; D-mycinose; and L-oleandrose, whose structures are given below:

Out of all the ‘sugar components’ present, at least one sugar is an amino-sugar, such as: D-desosamine; D-forosamine; and D-mycaminose, who structures are as depicted below.

The various important members of ‘macrolide antibiotics’ are, namely: Erythromycin, Clarithromycin, Arithromycin, Oleandomycin; Troleandomycin; and Spiramycins.

In general, these antibiotics essentially exhibit a narrow spectrum of antibacterial activity, most importantly against the Gram-positive microorganisms. It is, however, pertinent to mention here that the antibacterial spectrum of the aforesaid antibiotics resembles, but is not very much identical to, that of the penicillins; hence, they cater for an extremely valuable alternative or substitute for such patients who are found to be allergic to the penicillins. It is worthwhile mentioning at this point in time that Erythromycin is one of the most important and principal macrolide antibiotics presently employed in medicine.

Some of these antibiotics shall now be treated individually in the sections that follows:

3.6.1 Erythromycin

Synonyms Erythromycin A; Abomacetin; Ak-Mycin; Aknin; E-Base; EMU; E-Mycin; Eritrocina; Ery Derm; Erymax; Ery Tab; Erythromast 36; Erythromid; ERYC, Erycen; Erycin; Erycinum; Ermysin; Ilotycin; Inderm, Retcin; Staticin; Stiemycin, Torlamicina.

Biological Sources It is produced by cultures of Saccharopolyspora erythraea (formerly known as Streptomyces erythreus). Waksman and Henrici were the pioneer in finding this antibiotic in a soil sample collected from the Philippine Archipelago.

Erythromycin is, in fact, a mixture containing principally Erythromycin A. Together with small quantum of Erythromycins B and C.

Chemical Structure

E-Mycin (3R*, 4S*, 5S*, 6R*, 7R*, 9R*, 11R*, 12R*, 13S*, 14R*)-4-(2, 6-Dideoxy-3-C-methyl-3-0-methyl-a-L-ribo-herapyranosyl) oxy]-14-ethyl-7, 12, 13-trihydrox-3, 5, 7, 9, 11, 13-hexamethyl-6-[[3, 4, 6-trideoxy-3 (Dimethyl-amino)-β-D-xylo-hexopyranosyl] oxy] oxacyelotetradecane-2, 10-dione; (C₃₇H₆₇NO₁₃).

Characteristic Features

1. It is obtained as white or slightly yellow-crystals or powder, odourless or practically odourless, slightly hygroscopic in nature, having mp 135-140°C.

2. It is found to get resolidified with second mp 190-193°C.

3. It has specific optical rotation [α]_D²⁵-78° (C = 1.99 in ethanol).

4. It has uv_max (pH 6.3): 280 nm (ε 50).

5. Its dissociation constant is pKa1 8.8.

6. It usually shows basic reaction and readily forms salts with acids e.g., acetate, estolate, glucoheptanoate, lactobionate, propionate, stearate and the like.

7. Its solubility in water is nearly 2 mg . ml–1.

8. It is found to be freely soluble in alcohols, acetone, chloroform, acetonitrile, ethyl acetate; and

moderately soluble in solvent ether, ethylene dichloride and amyl acetate.

Uses

1. It exhibits a relatively broad spectrum of activity which usually overlaps the activity of penicillin.

2. It is found to be most effective against a host of Gram-positive cocci, namely: Enterococci,

Group A hemolytic streptococci, pneumococci, and Staphylococcus aureus, N. meningitidis and gonorrhoeae, Listeria, Corynebacterium diphtheria, acnes and certain specific strains of H. influenzae are also reported to be sensitive.

3. A low concentration of erythromycin also inhibit mycoplasma and the agent of Legionnaire’s disease*.

4. It inhibits the spirochaete Treponema pallidum and is an alternative to penicillin in the treatment of syphilis.

5. It is quite often regarded as the ‘drug-of-choice’ for undiagnosed pneumonias because it is found to be active against Streptococcus pneumoniae, Legionella and Mycoplasma pneumoniae.

6. It is extensively employed as an alternative to b-lactam antibiotics in soft-tissue infections, skin and in respiratory related diseases particularly in penicillin-allergic patients.

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* Legionnaire’s Disease: A severe, often total disease characterized by pneumonia, dry cough, mylagia and sometime gastrointestinal symptoms. It may occur in epidemic or sporadically and has become an important cause of nosocomia pneumonia. An organism, Legionella pneumophia, cause the disease when it is inhaled from aerosols produced by

air-conditioning units, shower heads etc.,

3.6.2 Clarithromycin

Synonyms Biaxin; Clathromycin; Klacid; Klaricid; Macladin; Naxy; Veclam; Zeclar; A-56268; TE-031.

Biological Source It is a semi-synthetic derivative of erythromycin which is obtained from Saccharopolyspora erythraea.

Chemical Features Erythromycin is fairly unstable under acidic environment whereby it undergoes degradation to inactive molecules through the 6-hydroxyl attacking the 9-carbonyl function to form a hemiketal (or hemiacetal) as shown below:

However, a similar reaction may also take place between the C-12 hydroxyl function and the C-9 carbonyl moiety.

In order to minimise this particular acid-instability semi-synthetic structural analogues of erythromycin have been developed by forming the corresponding 6-O-methyl derivative of erythromycin A, thereby blocking the possibility of hemiacetal formation completely.

Chemical Structure 
Clarithromycin is nothing but a simple structural variant of erythromycin A having a 6-O-methyl substituent.

6-O-Methylerythromycin; (C₃₈H₆₉NO₁₃).

Characteristic Features

1. It is obtained as colourless powder from a (1 : 2) mixture of chloroform and diisopropyl ether having mp 217-220°C (decomposes).

2. It is also obtained as crystals from ethanol with mp 222-225°C (Morimoto).

3. It has uv_max (CHCl₃) : 288 nm (ε 27.9).

4. It has specific optical rotation [α]_D²⁴-90.4° (C = 1 in CHCl₃).

5. It is found to be stable at acidic pH.

Uses

1. It is invariably used as an alternative to erythromycin for treating streptococcal pharyngitis, community-acquired respiratory tract infections, skin and soft tissue infections and an acute attack of sinusitis.*

2. It is found to be two-to-four times more active than erythronycin itself against a host of streptococci and staphylococci species; however, certain organisms that are resistant to erythromycin are also observed to be resistant to clarithromycin.

3. It exhibits a moderate activity against H. influenzae and N. gonorrhoea.

4. Clarithromycin is found to be influenced by Branhamella catarrhalis, Legionella pneumophilia, Mycoplasma pneumoniae, Chlamydia trachomatis and pneumoniae and Borrelia burgdorferi (agent of Lyme’s disease**).

5. It also shows activity against Mycobacterium avium and Mycobacterium intracellulare; and is mostly employed as primary agent for the treatment of disseminated mycobacterial infections.

3.6.3 Azithromycin

Synonyms Azitrocin; Sumamed; Trozocina; Zithromax; Zitromax; CP-62993; XZ-450.

Biological Source It is a semi-synthetic macrolide antibiotic related to erythromycin A which is obtained from Saccharopolyspora erythraae.

Chemical Structure Azithromycin is a tailor-made ring-expanded aza-macrolide wherein the carbonyl moiety at C-6 has been subjected to reduction; and this sort of minor alternation vis-a-vis the complex structure has significantly increased the activity when compared to the parent compound erythromycin A.

9-Deoxo-9a-methyl-9a-aza-9a-homoerythromycin A; (C₃₈H₇₂N₂O₁₂).

Characteristic Features

1. It is obtained as white crystals having mp 113-115°C .

2. It has specific optical rotation [α]₂₀^D -37° (C = 1 in CHCl₃).

Use

It is found to be active against staphylococci and streptococci but is more active than erythromycin against H. influenzae and some aerobic Gram-negative bacilli.

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* Sinusitis: Inflammation of a sinus, especially a paranasal sinus. It may be caused by various agents, includin viruses, bacteria or allergy:

** Lyme’s Disease: A multisystem disorder caused by the tick-transmitted spirochete Borhelia burgdorferi.

3.6.4 Oleandomycin

Synonyms Amymicin; Landomycin; Romicil.

Biological Source It is an antibiotic substance produced by fermentation cultures of Streptomyces antibioticus no. ATCC 11891.

Chemical Structure

Characteristic Features

1. It is obtained as white amorphous powder.

2. It has uv_max (methanol): 286-289 nm.

3. It is found to be freely soluble in methanol, ethanol, butanol, acetone; and almost insoluble in hexane, carbon tetrachloride, dibutyl ether.

Oleandomycin Hydrochloride (C₃₅H₆₁NO₁₂.HCl):

1. It is obtained as long needles from ethyl acetate having mp 134-135°C.

2. It has specific optical rotation [α]_D²⁵-54° (methanol).

3. It is freely soluble in water; and forms various crystalline hydrates.

Oleandomycin Triacetate Ester [Synonym Troleandomycin; Cyclamycin; Wytrion; Evramycin; Triocetin; TAO; NSC-108166.]

It is a semi-synthetic macrolide antibiotic prepared from oleandomycin wherein the three hydroxyl functions each at C-11, and the two sugar moieties replaced by the acetate groups.

1. It is obtained as crystals from isopropanol that yet decomposed at 176°C.

2. It is practically tasteless.

3. It has specific optical rotation [α]_D²⁵-23° (methanol).

4. It shows a dissociation constant pKa 6.6.

5. It is found to be soluble in water < 0.1 g per 100 ml.

Uses It is useful against a number of Gram-positive bacterial infections.

3.6.5 Spiramycins

Synonyms Selectomycin; Revamicina; Rovamycin; RP-5337.

Biological Sources Spiramycins are macrolides produced by cultures of Streptomyces ambofaciens from the soil of northern France.

Chemical Structure The mixture of spiramycins have been successfully separated into three different components termed as: Spiramycin I, II and III.

Characteristic Features

1. It is obtained as an amorphous base.

2. It has specific optical rotation [α]_D²⁰-80° (methanol).

3. It has uv_max (ethanol): 231 nm.

4. It is found to be slightly soluble in water; and soluble in most organic solvents.

Uses

1. It exhibits activity on Gram-positive organisms and rickettsiae.

2. It also shows cross resistance between microorganisms resistant to erythromycin and carbomycin.

Spiramycin I [C₄₃H₇₄N₂O­] [Synonym Foromacidin A]: It is obtained as crystals having mp ranging between 134-137°C, and specific optical rotation [α]_D²⁰-96°.

Spiramycin II [15] [Synonym Foromacidin B]: It is obtained as crystals having m_p130-133°C, and [α]_D²⁰-86°.

Spiramycin III [C₄₆H₇₈N₂O₁₅] [Synonym Foromacidin C]: It is also obtained as crystals having m_p ranging between 140-142°C, and [α]_D²⁰-98.4°.

Spetamycin III Diacetate: It is obtained as crystals from cyclohexane having mp 140-142°C; and specific optical rotation [α]_D²⁰-90.4°.

Use It is used for the treatment of toxoplasmosis, and also the infections caused by the protozoan Toxoplasma gondii.

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Source:Pharmacognosy And Pharmacobiotechnology By Ashutosh Kar