RECENT ADVANCES IN ANTIBIOTIC MACROLIDE

Presented by BIPIN UKEY

INTRODUCTION:The term macrolide is derived from the characteristic large lactone ( cyclic ester) ring found in these antibiotics.

The macrolides are a group of drugs (typically antibiotics) whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached.

CHEMISTRY
The macrolide antibiotic have three common chemical characteristics :-

A large lactone ring, A ketone group, A glycosidically linked amino sugar.

Usually the lactone ring has 12, 14 or 16 atoms in it and is often partially unsaturated, with an olefinic group conjugated with ketone function. They may have an, in addition to the amino sugar, a neutral sugar that is glycosidically linked to the lactone ring.

CLASSIFICATION Antibiotic macrolides:US FDA-approved : Ex. Azithromycin , Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Telithromycin. Not US FDA-approved: Ex. Josamycin, Kitasamycin, Midecamycin/midecamycin acetate, Oleandomycin, Solithromycin, Spiramycin , Troleandomycin , Tylosin.

KETOLIDES
Ketolides are a new class of antibiotics that are

structurally related to the macrolides. They are used to treat respiratory tract infections caused by macrolideresistant bacteria. Ketolides are especially effective, as they have two ribosomal binding sites; the newer fluoroketolides have three ribosomal interaction sites.
Ketolides include:

Ex.

Telithromycin, Oleandomycin, Cethromycin, Carbomycin, Solithromycin , Ansamycin.

Mechanism Of Action: The macrolide exert their antibacterial effect, which are usually bacteriostatic, via inhibition of bacterial protein biosynthesis. Specifically, the macrolide target the 50s ribosomal subunit; different member stop protein synthesis at varying stage of peptide chain elongation. The macrolide inhibit ribosomal peptidyl transferase activity . some macrolide also inhibit the translocation of the ribosome along the mRNA template.

Uses: Antibiotic macrolides are used to treat infections caused by Gram-positive bacteria, Streptococcus pneumoniae, and Haemophilus influenzae infections such as respiratory tract and soft-tissue infections.

Unlike penicillin, macrolides have been shown to be effective against mycoplasma, mycobacteria, some rickettsia, and chlamydia.

Resistance : The primary means of bacterial resistance to macrolides occurs by post-transcriptional methylation of the 23S bacterial ribosomal RNA. This acquired resistance can be either plasmidmediated or chromosomal, i.e., through mutation, and results in cross-resistance to macrolides, lincosamides, and streptogramins (an MLS-resistant phenotype).
Two other types of acquired resistance rarely seen include the production of drug-inactivating enzymes (esterases or kinases), as well as the production of active ATP-dependent efflux proteins that transport the drug outside of the cell. Azithromycin has been used to treat strep throat (Group A streptococcal (GAS) infection caused by Streptococcus pyogenes) in penicillin-sensitive patients, however macrolideresistant strains of GAS are not uncommon.

MIDECAMYCIN

(2S,3S,4R,6S)-6-{[(2R,3S,4R,5R,6S)-4-(dimethylamino)-5-hydroxy-6{[(4R,6S,7R,9R,10R,11E,13E,16R)-10-hydroxy-5-methoxy-9,16dimethyl-2-oxo-7-(2-oxoethyl)-4-(propanoyloxy)-1-oxacyclohexadeca11,13-dien-6-yl]oxy}-2-methyloxan-3-yl]oxy}-4-hydroxy-2,4dimethyloxan-3-yl propanoate

Midecamycin is a macrolide from Streptomyces mycarofaciens

antibiotic.

Synthesized

Mechanism of action:Midecamycin binds reversibly to 50S ribosomal subunit causing blockade of transpeptidation/translocation reactions, inhibition of protein synthesis and thus inhibition of cell growth. Midecamycin has similar uses to erythromycin but is less active.

Side effect:1. diarrhoea, 2. nausea, 3. stomach discomfort and 4. loss of appetite

DIRITHROMYCIN

2R,3R,6R,7S,8S,9R,10R,12R,13S,15R,17S)-9-{[(2S,3R,4S,6R)-4(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-3-ethyl-2,10-dihydroxy-7{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-15-[(2methoxyethoxy)methyl]-2,6,8,10,12,17-hexamethyl-4,16-dioxa-14azabicyclo[11.3.1]heptadecan-5-one

BRAND NAME(S): Dynabac

Dirithromycin is a macrolide glycopeptide antibiotic Dirithromycin is used to treat many different types of bacterial infections, such as bronchitis, pneumonia, tonsillitis, and skin infections.

Mechanism of action
Dirithromycin prevents bacteria from growing, by interfering with their protein synthesis. Dirithromycin binds to the 50S subunit of the 70S bacterial ribosome, and thus inhibits the translocation of peptides. Dirithromycin has over 10 times higher affinity to the subunit 50S than erythromycin.

Pharmacodynamics:Dirithromycin is a pro-drug which is converted non-enzymatically during intestinal absorption into the microbiologically active moiety erythromycylamine. Dirithromycin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections: Staphylococcus aureus (methicillin-susceptible strains only), Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, and Mycoplasma pneumonia

SIDE EFFECTS:1. 2. 3. 4. 5. Indigestion, Headache, Dizziness, Vomiting, Abdominal pain.

JOSAMYCIN

(2S,3S,4R,6S) -6- {[(2R,3S,4R,5R,6S) -6- {[(4R,5S,6S,7R,9R,10R,11E,13E,16R) -4- (acetyloxy)-10-hydroxy-5-methoxy-9, 16-dimethyl-2-oxo-7-(2-oxoethyl)-1oxacyclohexadeca-11, 13-dien-6-yl]oxy}-4-(dimethylamino)-5-hydroxy-2-methyloxan3-yl]oxy}-4-hydroxy-2, 4-dimethyloxan-3-yl 3-methylbutanoate

Mechanism of action
The mechanism of action of macrolides such as Josamycin is via inhibition of bacterial protein biosynthesis by binding reversibly to the subunit 50S of the bacterial ribosome, thereby inhibiting translocation of peptidyl tRNA. This action is mainly bacteriostatic, but can also be bactericidal in high concentrations. Macrolides tend to accumulate within leukocytes, and are therefore actually transported into the site of infection.

Side effects:1. 2. 3. 4. 5. Loss of hearing Tinnitus, Hives, Redness, disorder of urine out flow & jaundice

CETHROMYCIN

(1S,2R,5R,7R,8R,9S,11R,13R,14R)-8-[(2S,3R,4S,6R)- 4-Dimethylamino3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-1,5,7,9,11,13- hexamethyl-9[(E)-3-quinolin-3-ylprop-2-enoxy] -3,17-dioxa-15-azabicyclo[12.3.0 ]heptadecane-4,6,12,16-tetrone

Cethromycin is a ketolide antibiotic undergoing research for the treatment of community acquired pneumonia (CAP)and for the prevention of post-exposure inhalational anthrax, and was given an "orphan drug " status for this indication.

Mechanism of action:Inhibits bacterial protein synthesis by interacting close to the peptidyl transferase site of the 50S ribosomal subunit. The main binding sites are within domains II and V of the 23S rRNA.

Adverse effect:1. 2. 3. 4. 5. 6. 7. flushing, hypotension, bradycardia headache, dizziness, insomnia, vertigo

Kitasamycin

2-[(4R,5S,6S,7R,9R,10R,11E,13E,16R)-6-[(2S,3R,4R,5S,6R)-5-[(2S,4R,5S,6S)4,5-Dihydroxy-4,6-dimethyloxan- 2-yl]oxy-4-dimethylamino-3-hydroxy-6-m ethyloxan-2-yl]oxy-4,10-dihydroxy- 5-methoxy-9,16-dimethyl-2-oxo-1oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde

Kitasamycin is a macrolide antibiotic. It is produced by streptomyces kitasatoensis.

Mechanism of action:The mechanism of action of macrolides such as Kitasamycin A3 is via inhibition of bacterial protein biosynthesis by binding reversibly to the subunit 50S of the bacterial ribosome, thereby inhibiting translocation of peptidyl tRNA.

Pharmacology:Kitasamycin A3 is a macrolide antibiotic from Streptomyces narbonensis. The drug has antimicrobial activity against a wide spectrum of pathogens.s

Ansamycin

(9S,12E,14S,15R,16S,17R,18R,19R,20S,21S,22E,24Z)-6,16,18,20-Tetrahydroxy1'-isobutyl-14-methoxy-7,9,15,17,19,21,25-hepta-methyl-spiro[9,4-(epoxypen tadeca[1,11,13]trienimino)-2H-furo-[2',3':7,8]-naphth[1,2-d]imidazol-2,4'-piperi din]-5,10,26-(3H,9H)-trione 16-acetate

Ansamycins is a family of secondary metabolites that show antimicrobial activity against many gram-positive and some gram-negative bacteria and includes various compounds, among which: streptovaricins and rifamycins In addition, these compounds demonstrate antiviral activity towards bacteriophages and poxviruses.

Mechanism of action:Ansamycin acts via the inhibition of DNA-dependent RNApolymerase, leading to a suppression of RNA synthesis and cell death.