Chapter 8 Antibiotics

1
Chapter 8 Antibiotics

• Section 2. Tetracyclines
• Section 3. Aminoglycoside
• Section 4. Macrolides
• Section 5. Chloramphenicol

2
Antibiotics as disturber with the biosynthesis of
protein

• These antibiotics all target the bacterial
  ribosome and interfere in the process of
  translation of the messenger RNA into protein and
  thus block a fundamental process in bacterial
  metabolism.
• Inhibitors of 30s Ribosomal subunit
  Aminoglycosides and Tetracyclines
• Inhibitors of the 50s Ribosomal subunit
  Macrolides and Chloramphenicol

3
Tetracycline Antibiotics
4
Tetracyclines are produced by actinomyces (???),
which have broad-antibacterial spectrum. The
basic skeleton of tetracyclines is naphthacene
ring. Tetracyclines differing from each other
chemically only by substituent variation at
positions 5,6 and 7.
5
Tetracycline pharmacophore and numbering

• Positions at the bottom of the molecule (10,
  11, 1) and most of ring A (positions 2, 3, and 4)
  represent the invariant pharmacophore region of
  the molecule, where modifications are not
  tolerated without loss of antibiotic activity.

6
Mechanism of Action Tetracyclines inhibit
bacterial protein synthesis by blocking the
attachment of the t-RNA-amino acid to the
ribosome. Tetracyclines can also inhibit
protein synthesis in the host, but are less
likely to reach the concentration required
because eukaryotic (?????) cells do not have a
tetracycline uptake mechanism.
7
(No Transcript)
8
Tetracycline

• 6-Methyl-4-(dimethylamino)-3,6,10,12,12a-pentahydr
  oxy-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthaceneca
  rboxamide

9
Stability under acid condition

• The tetracycline molecule, as well as those that
  contain the 6ß-hydroxy group, is labile to acid
  and base degradation. At pH ?2.0, tetracycline
  eliminates a molecule of water with concomitant
  aromatization of ring C to form
  anhydrotetracycline.

10
Formation of 4-Epitetracycline

• At C-4 in acidic medium (pH 2-6), epimerization
  of the natural C-4 a-dimethylamino group to the
  C-4ß-epimer occurs. Under acidic conditions, a
  12 equilibrium is established in solution within
  a day.

11
Stability under base condition

• In basic medium, ring C of tetracycline is opened
  to form isotetracycline.

12
Formation of metal chelates

• Stable chelate complexes are formed by the
  tetracyclines with many metals, including
  calcium, magnesium, and iron. Such chelates are
  usually very insoluble in water.
• The affinity of tetracyclines for calcium causes
  them to incorporated into newly forming bones and
  teeth as tetracycline-calcium orthophosphated
  complexes. Deposits of these antibiotics in teeth
  cause a yellow discoloration.
• The tetracyclines are distributed into the milk
  of lactating mothers and will cross the placental
  barrier into the fetus.
• The possible effects of these agents on bones and
  teeth of the child should be considered before
  their use during pregnancy or in children under 8
  years of age.

13
Aminoglycoside Antibiotics
14
The aminoglycoside class of antibiotics contains
a pharmacophoric 1,3-diaminoinositol (1,3-?????)
derivatives
Streptamine 2-Deoxystreptamine
Spectinamine (???)
(2-?????) (????)
15
Chemistry
(N-Methyl-L-Glucosmine)
(Streptide)
(L-Streptose)

• Aminoglycosides are so named because their
  structures consist of amino sugars linked
  glycosidically. All have at least one
  aminohexose, and some have a pentose lacking an
  amino group.

16
Caution !

• It should be remember that penicillin and
  aminoglycoside antibiotics must never be
  physically mixted, because both are chemically
  inactivated to a significant degree on mixting.

17
Chemistry

• Aminoglycosides are strong basic compounds that
  exist as polycations at physiological pH. Their
  inorganic acid salts are very soluble in water.
  All are available as sulfates.
• The high water solubility of the aminoglycosides
  no doubt contributes to their pharmacokinetic
  properties. They distribute well into most body
  fluids but not into the ventral nervous system,
  bone, or fatty or connective tissues. They tend
  to concentrate in the kidneys and excreted by
  glomerular filtration. Aminoglycosides are
  apparently not metabolized in vivo.

18
Spectrum of activity

• Aminoglycosides are used for treatment of serious
  systemic infections caused by aerobic
  Gram-negative bacilli. Aerobic G-N and G-P cocci
  tend to be less sensitive thus the ßlactams and
  other antibiotics tend to be preferred for the
  treatment of infections caused by these
  organisms. Anaerobic bacteria are invariably
  resistant to the aminoglycosides.
• Streptomycin is the most effective of the group
  for the chemotherapy of tuberculosis.
• Under certain circumstances, aminoglycoside and
  ßlactams antibiotics exert a synergistic action
  in vivo against some bacterial strains when the
  two are administered jointly.

19
Mechanism of Action

• The mechanism of action of these antibiotics
  believed that they can inhibit the biosynthesis
  of protein of bacteria.
• At less than toxic doses, they bind to the
  protein portion of the 30S ribosomal subunit
  leading to mistranslation of RNA templates and
  the consequent insertion and wrong amino acids
  and formation so-called nonsense proteins.

20
(No Transcript)
21
Toxicity

• Their undesirable side effects severe
  ototoxicity and nephrotoxicity.
• 18 of 21 actress showing qianshou guanyin were
  caused deafness by aminoglycosides.

22
Streptomycin(???)
Streptomycin is the first aminoglycosides
isolated from Streptomyces griseus. There
are three basic centers in the structure.
23
(No Transcript)
24
(No Transcript)
25
Clinical Use

• Streptomycin was the first aminoglycoside
  isolated and the first antibiotic with potent
  activity against Mycobacterium tuberculosis and
  this antibiotic continues to be used to treat
  tuberculosis, but as a result of the development
  of resistance, now in combination therapy with
  other antibiotics.
• Streptomycin can also be used for the treatment
  of tularemia(???), plague(??) and leprosy(???).
• The aminoglycosides are highly water soluble and
  poorly absorbed orally. These antibiotics are
  therefore primarily delivered by intramuscular
  injection or intravenously.

26
Macrolide Antibiotics
27
Macrolide Antibiotics

• Naturally occurring macrolide antibiotics are
  grouped into three major groups of 12-, 14-, and
  16-membered macrolides with the aglycone
  consisting of 12-, 14-, and 16-atom cyclic
  lactone rings, respectively. For example,
  erythromycin A is a 14-membered macrolide (a
  14-atom cyclic lactone ring) and possesses
  desosamine and cladinose glycosidically linked to
  C-5 and C-3, respectively.

28
Mechanism of action

• The mechanism of action of macrolides is that it
  inhibits bacteria by interfering with programmed
  ribosomal protein biosynthesis by inhibiting
  translocation of amino acid m-RNA following
  binding to the 50s subunit.

29
(No Transcript)
30
Erythromycin (???)

• Erythromycin is an orally effective antibiotic
  discovered in 1952 in the metabolic products of a
  strain of Streptomyces eryyhreus(?????), it
  includes Erythromycin A, B, and C. The component
  A is used in clinic primarily.
• It is active for most G-P and some G-N.

31
Erythromycin

• A and B
• A C-12-OH
• B C-12-H

A and C A C-3"OCH3 C C-3"-OH
32
Extremely unstable under acid condition
33
Simply modification of erythromycin-Ester
Pro-drug
34
Strategy for erythromycin modification
35
(No Transcript)
36
Erythromycin derivatives
37
Telithromycin

• Telithromycin is the first ketolide(3-keto
  macrolide derivatives). It is prepared by
  removing the cladinose sugar from the C-3
  position of the erythronolide skeleton and
  oxidizing the remaining hydroxyl group to a keto
  group.

38

• In addition to the C-3 ketone, telithromycin has
  an aromatic N-substituted carbamate extension at
  position C-11 and C-12. This ring has an
  imidazo-pyridyl group attachment.
• Telithromycin possesses a 6-OCH3 group (like
  clarithromycin), avoiding internal
  kemiketalization with the 3-keto function and
  giving the ketolide molecule excellent acid
  stability.
• The ketolides are very active against respiratory
  pathogens, including erythromycin-resistant
  strains

39
Chloramphenicol Antibiotics
40
Chloramphenicol (??? )

• Chemical name
• D-(-)-threo-1-p-nitrophenyl-2-dichloroacetamido-1,
  3-propanediol

41
A molecule, with two chiral centers, has four
isomers (diastereomers).
42
Chloramphenicol is an antibiotic produced by
Streptomyces venezuelae and other soil bacteria
that was first discovered in 1947 and is now
exclusively produced synthetically. With two
chiral centers it is one of four diastereomers
only one of which (1R, 2R) is active.
43
Chemical properties
44
Chloramphenicol is bacteriostatic by inhibition
of protein biosynthesis. Its toxicities prevent
Chloramphenicol from being more widely used. The
major adverse effect of chloramphenicol is a risk
of fatal irreversible aplastic anemia that occurs
after therapy and does not appear to be related
to dose or administration route. Reversible bone
marrow suppression and several other adverse
effects including gastrointestinal problems,
headache, and mild depression have also been
noted.
45
(No Transcript)
46
Usage

• Despite potentially serious limitations,
  Chloramphenicol is an excellent drug when used
  carefully. Its special value is in typhoid (??)
  and paratyphoid fever(???), Haemophilus infection
  , pneumococcal (????) and meningococcal
  meningitis(???) in ß-lactam allergic patients,
  anaerobic(???) infection , rickettsial
  infections, and so on.

47
Synthesis
48
Chloramphenicol Palmitate (?????)
Chloramphenicol Palmitate is the palmitic acid
ester of chloramphenicol. It is a tasteless
prodrug of chloramphenicol intended for pediatric
use. The ester must hydrolyze in vivo following
oral absorption to provide the active form.
49
 Chloramphenicol Sodium Succinate (??????)
Chloramphenicol sodium succinate is the
water-soluble sodium salt of the hemisuccinate
ester of chloramphenicol. Because of the low
solubility of chloramphenicol, the sodium
succinate is preferred for intravenous
administration. The availability of
chloramphenicol from the ester following
intravenous administration is estimated to be 70
to 75.
50
Summary

• Tetracyclines
• Aminoglycosides
• Macrolides
• Erythromycin
• Structure modification of semi-synthetic
  erythromycin
• Chloramphenicol
• Mechanism of action

51

• Question
• 1. Why is the erythromycin A unstable in acidic
  condition?
• 2. What is the difference of the action mechanism
  of antibiotics?
• Assignment
• 1.Read textbook pp334-355,360-361
• 2.Do homework Exercises of medicinal chemistry
  p96 Type A and????????,???