This document discusses various aminoglycoside antibiotics, including their structures, mechanisms of action, and examples. It describes how streptomycin was the first antibiotic in this group discovered by Waksman in 1944 from Streptomyces griseus bacteria. Aminoglycosides have broad-spectrum activity against gram-negative bacteria but can cause nephrotoxicity and ototoxicity. Examples discussed include kanamycin, neomycin, gentamicin, and tobramycin. The document also summarizes the structures, uses, and mechanisms of several other classes of antibiotics, including tetracyclines.

1. Dr. Aejaz Ahmed HOD & Associate Professor
Department of Pharmaceutical Chemistry
ALI-ALLANA COLLEGE OF PHARMACY, AKKALKUWA
Medicinal Chemistry –III
UNIT-I

2. AMINOGLYCOSIDE ANTIBIOTICS
• The aminoglycoside antibiotics contain one or more amino sugars
linked to an aminocytitol ring by glycosidic bonds.
• These are broad-spectrum antibiotics; in general, they have greater
activity against gram-negative than gram-positive bacteria.
• The development of streptomycin, the first antibiotic of this group,
was a well-planned work of Waksman (1944) and his associates, who
isolated it from a strain of Streptomyces griseus.
• The aminoglycoside can produces severe adverse effects, which
include nephrotoxity, ototoxicity, and neuro effects.
• These properties have limited the use of aminoglycoside
chemotherapy to serious systemic indications. Some aminoglycosides
can be administered for ophthalmic and topical purposes.

3. Examples of aminoglycoside antibiotics
The organism that produces streptomycin, S. griseus, also produces several other
antibiotic compounds: hydroxystreptomycin, mannisidostreptomycin, and
cycloheximide.
Among the many antibiotics isolated from that genus, several are compounds closely
related in structure to streptomycin. Six of them—kanamycin, neomycin, paromomycin,
gentamicin, tobramycin, and netilmicin— currently are marketed in the United States.
Amikacin, a semisynthetic derivative of kanamycin A, has been added, and it is possible
that additional aminoglycosides will be introduced in the future.

4. • Mode of action of Aminoglycosides :
• The aminoglycosides exhibit bactericidal effects as a result of several
phenomena.
• Ribosomal binding on 30s and 50s subunits as well as the interface
produces misreading; this disturbs the normal protein synthesis. Cell
membrane damage also plays an integral part in ensuring bacterial cell
death.
• The binding of streptomycin and other aminoglycosides to ribosomes also
causes misreading mutations of the genetic code, apparently resulting from
failure of specific aminoacyl RNAs to recognize the proper codons on
messenger RNA (mRNA) and hence incorporation of improper amino acids
into the peptide chain.

5. Spectrum of Activity
• The aminoglycosides are classified as broad spectrum antibiotics, their greatest
usefulness lies in the treatment of serious systemic infections caused by aerobic
Gram-negative bacilli
• The choice of agent is generally between kanamycin, gentamicin, tobramycin,
netilmicin, and amikacin. Aerobic Gram-negative and Gram-positive cocci (with the
exception of staphylococci) tend to be less sensitive; thus, the beta-lactams and
other antibiotics tend to be preferred for the treatment of infections caused by
these organisms.
• Streptomycin is the most effective of the group for the chemotherapy of TB,
brucellosis tularemia, and Yersinia infections.
•Paromomycin is used primarily in the chemotherapy of amebic dysentery
•Under certain circumstances, aminoglycoside and beta-lactam antibiotics exert a
synergistic action in vivo against some bacterial strains when the two are
administered jointly.
Penicillin G and Streptomycin (or Gentamicin or Kanamycin) tend to be more effective than
either agent alone in the treatment of enterococcal endocarditis.

6. • Streptomycin and Dihydrostreptomycin
Streptomycin sulphate is a white hygroscopic powder, very soluble in water, and
practically insoluble in ethanol. The organism, S. griseus, releases the other
substances, such as hydroxy streptomycin, mannisidostreptomycin, and
cycloheximide, but do not reach up to the required activity/potency level. The
development of resistant strains of bacteria and chronic toxicity constitutes major
drawbacks of this category. It is an aminoglycoside antibacterial also used as an
antitubercular drug.
Properties and uses:

7. Gentamycins
Properties and Uses:
Gentamycin is a mixture of C1, C2, and C1A compounds, obtained commercially from
Micromonospora purpurea. Gentamycin sulphate exists as white hygroscopic powder,
soluble in water, and practically insoluble in alcohol, although it is a broad-spectrum
antibiotic. It is used in the treatment of infections caused by gram-negative bacteria of
particular interest and has a high degree of activity against P. aeruginosa, where the
important causative factor is burned skin. It is used topically in the treatment of
infected bed-sores, pyodermata, burns, and in the eye infection.

8. Netilmicin Sulfate
• Netilmicin sulfate, 1-N-ethylsisomicin
(Netromycin), is a semisynthetic derivative
prepared by reductive ethylation138 of
sisomicin, an aminoglycoside antibiotic
obtained from Micromonospora inyoensis.139
Structurally, sisomicin and netilmicin resemble
gentamicin Cla, a component of the
gentamicin complex.

9. Tobramycin
• The most important property of tobramycin is its activity
• against most strains of P. aeruginosa, exceeding that of
gentamicin by twofold to fourfold. Some gentamicin-resistant
• strains of this troublesome organism are sensitive to
tobramycin, but others are resistant to both antibiotics.137
Other Gram-negative bacilli and staphylococci are generally
more sensitive to gentamicin. Tobramycin more closely
resembles kanamycin B in structure (it is 3-deoxykanamycin B).

10. Structure–Activity Relationships
• Ring I is crucially important for characteristic Broad-spectrum
antibacterial activity, and it is the primary target for bacterial
inactivating enzymes.
• It is convenient to discuss sequentially aminoglycoside SARs in terms
of substituents in rings I, II, and III.
• Few modifications of ring II (deoxystreptamine) functional groups are
possible without appreciable loss of activity in most of the
aminoglycosides.
•Ring III functional groups appear to be somewhat less sensitive to
structural changes than those of either ring I or ring II. Although the 2-
deoxygentamicins are significantly less active than their 2-hydroxyl
counterparts, the 2-amino derivatives (seldomycins) are highly active.
The 3-amino group of gentamicins may be primary or secondary
with high antibacterial potency. Furthermore, the 4- hydroxyl group may
be axial or equatorial with little change in potency.

11. Tetracycline:

12. Tetracycline's:
- A broadest spectrum antibiotics.
- The first of these compounds was Chlortetracycline
followed by Oxytetracycline and tetracycline.
• The tetracyclines are obtained by fermentation
procedures from Streptomyces spp. or by chemical
transformations of the natural products.

13. Spectrum of Activity
• The tetracyclines have the broadest spectrum of activity
of any known antibacterial agents.
• They are active against a wide range of Gram-positive
and Gram-negative bacteria, spirochetes, mycoplasma,
rickettsiae and chlamydiae.
• Their potential indications are, therefore, numerous.
• Because of incomplete absorption and their
effectiveness against the natural bacterial flora of the
intestine, tetracyclines may induce super infections
caused by the pathogenic yeast Candida albicans.

14. Types of Tetracycline
a) Naturally occurring:
1-tetracycline 2-chlortetracycline
3-oxytetracycline 4-demeclocycline

15. Semisynthetic occurring:
• 1-doxycycline 2-minocycline
• 3-meclocycline 4-lymecycline
• 5-methacycline 6-rolitetracycline

16. Structure and chemical characteristics
•

17. Structure Activity Relationship

18. •
R5 R4 R3 R2 R1.
Chlortetracycline H H OH CH3 Cl
Oxytetracycline H OH OH CH3 H
Tetracycline H H OH CH3 H
Demethyl chlortetracycline H H OR H CI
Rolitetracycline + H OH CH3 H
Metacycline H OH CH2 H
Doxycycline H OH H CH3 H
Minocycline H H H N(CH3) 2

19. • Retention of the configuration of the asymmetric
centres C-4, C-4a and C-12a is essential, whereas the
configurations at C-5, C-5a and C-6 may be altered:
• 1- The amide hydrogen may be replaced with a methyl
group, but larger groups have a deleterious effect
except for those which are eliminated spontaneously
in water .

20. • 2-The dimethyl amino group may be
replaced by a primary amino group
without loss of in vitro activity but all other
changes so far lead to decreased
bacteriostatic action .

21. • The hydrophobic part of the molecule
from C-5 to C-9 may be altered in various
ways:
• modifications at C-6 and C-7 in particular
afford products having greater chemical
stability.
• increased antibiotic activity and more
favourable pharmacokinetics

22. • Dehydrogenation to form a double bond
between C-5a and C-11a markedly
decreases activity
• Polar substituents at C-5 and C-6
contribute decreased lipid versus water
solubility to the tetracycline

23. • . The drugs are amphoteric, meaning they
will form salts with both strong acids and
bases. Thus, they may exist as salts of
sodium or chloride.

24. Spectrum of Activity:
-The tetracyclines are broad-spectrum antibiotics.
-They are active against the following
microorganisms:
1_ gram-positive and gram-negative bacteria
2_ spirochetes
3_ mycoplasmas,
4_ rickettsiae,
6_ Candida albicans

25. 7_Mycoplasma pneumoniae
8_Chlamydia trachomatis
9_Borrelia recurrentis.
10_Yersinia pestis
11_Vibrio cholerae
12_ Campylabacter fetus
13_Brucella specie
14_Streptococcus pneumoniee.
15_Neisserie gonorrhoeae

26. Mechanism of action:

27. Mechanism of resistance :
There are three types of tetracycline
resistance:
1) Tetracycline efflux.
2) Ribosomal protection.
3)Tetracycline modification.

28. Types of tetracyclines:
1-Demeclocycline:

29. Total Synthesis of the Tetracyclines:

31. Uses:
-treat cancer patients with SIADH.
-treat hyponatremia.
-combined with hydrocortisone in a paste used
by dentists .
-treat trachoma.

32. Side effect:
Dermatological:-Skin reactions, photosensitivity
GIT:-nausea, vomiting, and diarrhea.
CNS:-Dizziness,visualdisturbances .
Immune System:-allergic reactions.
Other:-yellowish-grayish-brown discoloration of the
teeth.

33. Pharmacodynamics/Kinetics:
-Absorption: ~50% to 80%.
-Protein binding: 41% to 50%
-Metabolism: Hepatic.
-Half-life elimination: 10-17 hours
-Time to peak, serum: 3-6 hours
-Excretion: Urine

34. 2-Chlortetracycline:
Uses:
-used as antibacterial and antiprotozoal agent.
-In veterinary medicine, it is commonly used
to treat conjunctivitis in cats.

35. 3-Oxytetracycline:
Uses:
-treat Spirochaetal infection.
-treating Non-Specific-Urethritis.
-treating Clostridial wound infection and Anthrax.

36. Side effects:
-Local irritation after intramuscular injection.
-Gastrointestinal:-anorexia, nausea, vomiting.
-Renal toxicity.
-Hypersensitivity reactions: Urticaria.
-Blood: Hemolytic anemia, thrombocytopenia,
neutropenia

37. 1-tetracycline:
Uses:
-Tetracycline's primary use is for the
treatment of acne vulgaris and rosacea.
-It is also used to treat a very wide range of
infections.

38. Side effects:
-Gastrointestinal: anorexia, nausea,
vomiting, diarrhea,
-Skin: rashes, dermatitis.
-Renal Toxicity
-Hepatic Cholestasis:
-Hypersensitivity
Reactions:Anaphylaxis,
Miscellaneous: Dizziness and headache

39. 4- Minocycline:
Uses:
-typhus fever and Q fever.
-Psittacosis Trachoma
-Nongonococcal urethritis.
-Brucellosis.

40. Side effects:
-Hypersensitivity reactions:Urticaria,anaphylaxis.
-GI :Anorexia, nausea, vomiting, diarrhea.
-Hepatic toxicity: Hyperbilirubinemia.
-Respiratory:Cough, dyspnea.
-Blood:Agranulocytosis, hemolytic anemia.
-CNS: Convulsions, dizziness,sedation.
-Oral cavity discoloration.

41. Pharmacokinetics:
-rapidly absorbed from the GIT.
-The peak plasma concentrations slightly
decreased.
-serum half-life ranged from 11 to 16 hours in
hepatic dysfunction, and from 18 to 69 hours
with renal dysfunction.

42. 5-doxycyclines
Uses:
used in the treatment of chronic adult
periodontitis.

43. Side Effects:
-Nausea, Vomiting,Diarrhea.
-photosensitivity, rash.
-dyspepsia
-dysphagia.
-Watery diarrhea
-Bloody stools

44. Drug interaction of tetracyclines::
antacids containing aluminum,
calcium, or magnesium, and
iron-containing preparations
Impaire the Absorption of
tetracyclines
anticoagulant therapy Because tetracyclines have
been shown to depress plasma
prothrombin activity, patients
who are on anticoagulant
therapy may require downward
adjustment of their
anticoagulant dosage.
bacteriostatic drugs interfere with the bactericidal
action of penicillin, it is
advisable to avoid giving
tetracycline-class drugs in
conjunction with penicillin.

45. oral contraceptives Concurrent use of tetracyclines
with oral contraceptives may
render oral contraceptives less
effective.
ergot alkaloids or their
derivatives are given with
tetracyclines.
Increased risk of ergotism
Bile acid sequestrants May decrease tetracycline
absorption
Iron preparations May decrease absorption of
tetracyclines

46. Thank You