Aminoglycosides, Macrolides, Chloramphenicol & Rifamycin( Rifampicin)

1. Chilkur Balaji College of Pharmacy
R.V.S Nagar, Aziz Nagar, Moinabad.
S.SEETARAM SWAMY, M.Pharm.,
Asst. professor,
Dept. of Pharmaceutical Chemistry,
Chilkur Balaji College of Pharmacy.
E-mail:seetaram.443@gmail.com
Aminoglycosides, Macrolide, Chloramphenicol

2. Antibiotics are substances produced by microorganisms, which selectively
suppress the growth of or kill other microorganism at very low
concentration.
CONTENTS
1. Aminoglycosides
a) Introduction
b) Mechanism of action
c) Toxicity
d) Therapeutic uses
2. Macrolides
3. Chlorampehenicol
4. Rifampicin

3. o Amino glycoside antibiotics contain an amino cyclitol moiety to which amino sugars
are linked glycosidically.
o They may be more correctly called aminocyclitol antibiotics.
o Aminoglycosides are a group of antibiotics effictive against gram+ve and gram-ve
organisms as well as micoplasma.
o Most of the aminoglycosides antibiotics are dirived from genus streptomycesspecies,
important one is streptomycin.
o Aminoglycoside antibiotics are also referred as aminocyclitol antibiotics, because they
consist of a highly substituted ring called aminocyclitol ring i.e.1,3 di amino cyclohexane
central ring.
o All Aminoglycosides in this class possess one amino hexose sugar. But some antibiotics
like streptomycin, neomycin, paramomycin possess a pentose sugar.
AMINOGLYCOSIDES

4. CLASSIFICATION
Systemic aminoglycosides
Streptomycin
Amikacin
Gentamicin
Kanamycine
Tobramuycin
Sisomicin
Topical aminoglycosides
Neomycin
Framycetin

5. STREPTOMYCIN
Streptomycin is the first aminoglycoside antibiotic which
was isolated from the actinomycetes bacteria
STREPTOMYCES GRISEUS and several related soil
microorganisms.
Streptomycin was first discovered in 1943 by SELMAN
ABRAHAM WAKESMAN and received a Nobel prize in 1952.
It was introduced primarily for the treatment of
tuberculosis.
Chemistry:
Physico-chemical properties:
Colour : colourless.
Odour : odourless.
State : Streptomycin sulphate and streptomycin chloride
available in the form of white powdery solid.
Solubility : Easily soluble in water insoluble in acetone.
Stability : It is stable at a temp. less than 28 ̊C and solutions
of streptomycin are stable at pH (4.5-7).

6.  Streptomycin is made up of 3 basic structural units called…
1. Streptidine(a diguanidino compound)
2. Streptose (a aldose sugar)
3. N-methyl-L-glucosamine.
O
H
OH
H
H
CH2OH
HOH
NHCH3
O
OH
CHO
CH3
H OH
H
H NH.C.NH2
H
H
OHH
OH
HNH.C.NH2
H OH
O
NH
NH
N-methyl-L-glucosamine
Streptose
Streptidine

7. O
H
OH
H
H
CH2OH
HOH
NHCH3
O
OH
CHO
CH3
H OH
H
H
OH
NH.C.NH2
H
H
OHH
OH
HNH.C.NH2
H OH
OH
NH
NH
N-methyl-L-glucosamine
Streptose
Streptidine
STREPTOMYCIN
Acid
Hydrolysis
C21H39N7O12
N-methyl-L-glucosamine Streptose
HydrolysisAlkaline
Hydrolysis
H
OH
NH2
H
H
OHH
OH
HNH2
H OH
Streptamine
HYDROLYSIS OF STREPTOMYCIN

8. DIHYDROSTREPTOMYCIN
 The only difference in the structure of streptomycin and dihydrostreptomycin is
the presence of a hydroxyl alcoholic group(-CH20H) in place of –CHO group of
Streptose moiety (the –CHO group of streptomycin is replaced by –CH2OH group).
 It is a semi-synthetic derivative obtained by the catalytic hydrogenation of
Streptomycin.
It has similar mechanism of action, pharmacokinetic aspects and toxicological
properties as that of streptomycin.

9. IMPORTANCE OF DIHYDROSTREPTOMYCIN:
 Treatment of tuberculosis in various animals.
 It is less neurotoxic than streptomycin but high
frequency of ototoxicity in humans.
 It is used in combination with procaine penicillin
to treat systemic infections.
 It is not recommended for humans as it is
ototoxic and hence mostly used for veterinary
purposes for the treatment of systemic
infections.

10. O
H
OH
H
H
CH2OH
HOH
NHCH3
O
OH
CH2OH
CH3
H OH
H
H NH.C.NH2
H
H
OHH
OH
HNH.C.NH2
H OH
O
NH
NH
N-methyl-L-glucosamine Streptidine

11. • Aminoglycosides binds to specific 30S – 50S subunit ribosomal proteins.
Protein synthesis is inhibited by them in at least three ways:
1.They Block the formation of initiation 70S ribosomal
mRNA complex
2.They induce misreading of the code on the mRNA template
Causes incorporation of incorrect amino acids into peptide
resulting in a nonfunctional or abnormal protein synthesis.
3.Inhibit translocation
11
MECHANISM OF ACTION

12. A. Ototoxicity
 Auditory (Loss of hearing) or vestibular
damage(dizziness, vertigo) or both.
 Neomycin, kanamycin, and amikacin
are the most ototoxic drugs,
Streptomycin and gentamicin are the
most vestibulo toxic.
B. Nephrotoxicity
 Aminoglycosides are mainly excreted by
glomerular filtration and can be stored
up in kidney. It can cause acute renal
insufficiency and tubular necrosis.
 Neomycin is the most nephrotoxic drug,
streptomycin is the least one.
C. Neuromuscular blockade
D. Skin reactions (Hypersensitivity
reactions)
 Skin rash, fever, eosinophilia and
anaphylactic shock. 12
TOXICITY

13. 13

14. Macrolide antibiotics are so named as they possess a macrocyclic lactone usually
having 12 to 17 atoms.
3 common chemical features they are:
1. a macro cyclic lactone, usually having 12 to 17 atoms
2. a ketone group.
3. One or two amino-sugars linked to the nucleus.
MACROLIDES
Macrolide antibiotics contain a many-membered lactone ring (14-membered rings for
erythromycin & clarithromycin and a 15-membered ring for azithromycin).
SOURCE:
These are produced by streptomyces
species and the products of
actinomycetes.
The presence of the dimethyl amino moiety on the sugar residue, which explains the
basicity of these compounds and consequently formation salts.

15. CLASSIFICATION:
Narrow spectrum:
Erythromycin (Streptomyces erythreus)
Broad spectrum:
Clarithromycin
Roxithromycin
Azithromycin are semi-synthetic derivatives of erythromycin.

17. MECHANISM OF ACTION

18. Hypersensitivity reactions (drug fever, skin rashes)
Gastrointestinal effects (Nausea, vomiting, and diarrhoea)
Hepatitis with cholestatic jaundice.
Mycoplasma pneumoniae Infections
Legionnaires' Disease
Diphtheria
Streptococcal Infections
Staphylococcal Infections
Campylobacter Infections
Helicobacter pylori Infection
Tetanus
Syphilis
Mycobacterial Infections
THERAPEUTIC USES
ADVERSE EFFECTES

19. Chloramphenicol / Chloromycetin is a broad spectrum antibiotic
isolated from Streptomyces venezuelae.
It has a nitrobenzene moiety that is responsible for antibacterial
activity and the bitter taste.
CHLORAMPHENICOL
SPECTRUM OF ACTIVITY:
 Active against S. typhi, H. influenzae, S. pneumoniae, B. fragilis.
 Less active against Chlamydia, Spirochetes while more against Klebsiella, B. pertussis.

20. 1. Chloramphenicol is a bacteriostatic by inhibiting protein synthesis.
2. It prevents protein chain elongation by inhibiting the peptidyl transferase
activity of the bacterial ribosome.
3. Inhibits protein synthesis by binding to 50 S ribosomal subunit of the microbe.
MECHANISIM OF ACTION

21. CO2N
O
CH3
Br2/CH3COOH
Bromination
NO2 C
H2
C
O
Br
Hexamine
O2N C
H2
C
O
NH2
O2N C CH2
O HN C CH3
O
Acetylation
(CH3CO)2O
O2N C C
H
O
CH2
HN C CH3
OH
HCHO
O2N
H
C
OH
C
H
HN
CH2
C
OH
CH3
O
Aluminium
isopropoxide
H
C
OH
C
H
NH2
CH2
OH
HCl/H2O
O2N
H2
C C
H
NHCOCHCl2
CH2
OH
O2N
Chloramphenicol
Chloroacetyl
chloride
Hydrolysis
Cl2CHCOCl
O
p-nitro acetophenone
Synthesis of Chloramphenicol

22. 1. Bone marrow toxicity
a) Bone marrow suppression
b) Aplastic anemia
2. Gray baby syndrome
3. Hypersensitivity reactions
4. Neurotoxic reactions
5. Leukemia
ADVERSE EFFECTES

23. THERAPEUTIC USES
1. Chloramphenicol has a wide range activity that includes gram+, gram-, aerobic
and anaerobic bacteria
2. Typhoid Fever ( Salmonella typhi)
3. Bacterial Meningitis (Chloramphenicol is active against the three main bacterial
causes of meningitis: Neisseria meningitidis, Streptococcus pneumoniae, and
Haemophilus influenzae)
4. Anaerobic Infections
5. Rickettsial Diseases
6. Brucellosis

24.  Refamycins are a group of macrocyclic antibiotics which are produced by Streptomyces
mediterranei.
 Eventually 7 rifamycins were developed they are Rifamycin A,B,C,D,E,S,SV.
 Refampicin is a semi-synthetic rifamycin made from Rifamycin-B isolated from
STREPTOMYCES MEDITERRANEI in 1957.
 Among the various rifamycins, rifamycin-B was the first Commercial product.
REFAMPICIN

25. It acts by inhibiting DNA-dependent RNA polymerase(DDRP)of mycobacteria and
other microorganisms by binding strongly to their β-subunits viz ( α, α1, β, β1 and
sigma) and there by suppression of inhibiting the m-RNA synthesis
 Refamycins inhibit the enzyme RNA polymerase and prevent RNA synthesis. Than in
turn prevent protein synthesis.
 So they are useful in treating tuberculosis, leprosy, Mycobacterium avium complex
(MAC) infection and Staphylococcus infections.
MECHANISIM OF ACTION

26. Hepatotoxic - hepatitis, liver failure in severe cases
Respiratory – breathlessness
Abdominal - nausea, vomiting, abdominal cramps.
Flu-like symptoms - with chills, fever, headache.
Certain bodily fluids, such as urine and tears, to become orange-red in color.
ADVERSE EFFECTES

27.  Refampicin is used as a first line drug in the treatment of
tuberculosis. As most of the tubercle bacilli develop resistance to
Refampicin. It is used in combination with other anti-tubercular
drugs in the MULTIPLE DRUG THERAPY to minimize the problem.
 It is also used the treatment of leprosy.
 Infection like endocarditis (inflammation of membrane lining
the heart.)
 Oesteomyelitis(inflammation of bone)
 It is used in the first-line therapy of brucellosis in combination
with doxycline.
 It is also an excellent drug for Pneumonia.
 It is also used in combination with dapsone in Treating leprosy.
THERAPEUTIC USES

28.  Most species of bacteria develop resistance to Refampicin.
 Use of single drug Refampicin for tuberculosis will not be effective.
 That’s why it is used in combination with other anti-tubercular drugs in multidrug
therapy.
 Drugs used most commonly to treat TB include Isoniazid, Refampicin, Ethambutol and
Pyrazinamide.
MULTI DRUG THERAPY (MDT)

29. Two phases of drug therapy are generally used:
 Initial phase: In this phase 3 drugs namely Refampicin, isoniazid, Pyrazinamide are
used. some times ethambutol drug is used .
All these drugs used for 2 months. (e.g: AKT4)
 Continuation phase:-Two drugs i.e. Refampicin and isoniazid are to be used for a time
period of the next 4months. (e.g: R-Cinex-600)