Microbiology: A Clinical Approach © Garland Science CHAPTER 19 ANTIBIOTICS © CDC / Gilda L. Jones.
Chapter 8 Antibiotics 03 (1)
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Chapter 8 Antibiotics
Section 2. Tetracyclines
Section 3. Aminoglycoside
Section 4. Macrolides
Section 5. Chloramphenicol
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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 an
d Chloramphenicol
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Tetracycline Antibiotics
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Tetracyclines are produced by actinomyces ( 放线菌 ),
which have broad-antibacterial spectrum. The basic s
keleton of tetracyclines is naphthacene ring. Tetracy
clines differing from each other chemically only by su
bstituent variation at positions 5,6 and 7.
R3 R2 R1 NOH
CONH2OOHO
OH
OH
HH
R4
123
45678
910 11 12
O
OOH
R3 R2
H
H R1
H
OH2N
OH
N
H
R4
OH
HO
ÍÁùËØ£¨Oxytetracycline£© R1 = -OH R2 = -OH R3 = -CH3 R4 = -H
½ðùËØ£¨Chlotetracycline£© R1 = -H R2 = -OH R3 = -CH3 R4 = -Cl
ËÄ»·ËØ£¨Tetracycline£© R1 = -H R2 = -OH R3 = -CH3 R4 = -H
ABCD
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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.
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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 ( 真核状态的 ) cells do not have a tetracycline uptake mechanism.
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Tetracycline
6-Methyl-4-(dimethylamino)-3,6,10,12,12a-
pentahydroxy-1,4,4a,5,5a,6,11,12a-octahydro-2-
naphthacenecarboxamide
OH O
OH
H H
OH
OH
O
OH
CONH2
N(CH3)2
1
2
345
67
8
9
10 11 12
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Stability under acid condition The tetracycline molecule, as well as those that contain the 6
β-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.
+N
OH
CONH2OH
OHHH
OH OO
H+ - H2O
- H+
OH NOH
CONH2OH
OHHH
OH O O
OH2+ N
OH
CONH2OH
OHHH
OH OO
NOH
CONH2
OHH
OH OH O O
ÍÑË®Îï
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Formation of 4-Epitetracycline At C-4 in acidic medium (pH 2-6), epimerization of the “natura
l” C-4 α-dimethylamino group to the C-4β-epimer occurs. Under acidic conditions, a 1:2 equilibrium is established in solution within a day.
OH NOH
CONH2OOHO
OHHH
OH
OHOH
CONH2OHOHO
OHHH
OH
H+N
OH
CONH2OHOHO
OHHH
OH
N
O
OH
CONH2OOHO
OHHH
OH
N
OH
4-Epitetracycline
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Stability under base condition
In basic medium, ring C of tetracycline is opened to form isotetracycline.
OH-
OH NOH
CONH2OH
OHHH
OH OO
O- NOH
CONH2OH
OHH
OH OO
NOH
CONH2
OH
OH
O
O OO
HN
OH
CONH2O-
OH
OH
O
O O
HN
OH
CONH2O-O
OH
OH
O H
O
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Formation of metal chelates
OH O
OH
H H
OH
OH
O
OH
CONH2
N(CH3)2Mn+
OH O
OH
H H
O
OH
O
OH
CONH2
N(CH3)2
Mn+
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.
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Aminoglycoside Antibiotics
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The aminoglycoside class of antibiotics contains
a pharmacophoric 1,3-diaminoinositol (1,3- 二氨基肌醇 ) derivatives
Streptamine 2-Deoxystreptamine Spectinamine
( 链霉胺 ) (2- 脱氧链霉胺 ) ( 放线菌胺 )
NH NH2
NH
OH
OH
NH
H2NNH
HOHO
NH2
OH
H2N
HOHO
NHOH
HN
HOHO
HO
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Chemistry
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.
( L-Streptose )
( Streptide )
( N-Methyl-L-Glucosmine )
NH NH2
NH
OH
OH
NH
H2NNH
OHO
ONHCH3
HO
HOH2C
HO
O
HO
OHC
OCH3
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Caution ! It should be remember that penicillin and ami
noglycoside antibiotics must never be physically mixted, because both are chemically inactivated to a significant degree on mixting.
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Chemistry Aminoglycosides are strong basic compounds that exist a
s 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.
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Spectrum of activity Aminoglycosides are used for treatment of serious syste
mic infections caused by aerobic Gram-negative bacilli. Aerobic G-N and G-P cocci tend to be less sensitive; thus the β–lactams 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 β–lactams antibiotics exert a synergistic action in vivo against some bacterial strains when the two are administered jointly.
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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.
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Toxicity Their undesirable side effects: severe ototoxicity and nephroto
xicity. 18 of 21 actress showing “qianshou guanyin” were caused deaf
ness by aminoglycosides.
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Streptomycin( 链霉素 )
Streptomycin is the first aminoglycosides isolated from
Streptomyces griseus.
There are three basic centers in the structure.
HOOH
HN NH2
NH
OHHN
H2NNH
OO
CHOO
HOHO
OHO
OHNHCH3
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Clinical Use Streptomycin was the first aminoglycoside isolated a
nd 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 (野兔病) , plague (瘟疫) and leprosy( 麻风病 ).
The aminoglycosides are highly water soluble and poorly absorbed orally. These antibiotics are therefore primarily delivered by intramuscular injection or intravenously.
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Macrolide Antibiotics
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Macrolide Antibiotics Naturally occurring macrolide a
ntibiotics 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.
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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.
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Erythromycin ( 红霉素)
Erythromycin is an orally effective antibiotic discovered in 1952 in the metabolic products of a strain of Streptomyces eryyhreus( 红色链丝菌 ), 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.
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Erythromycin
A and B
A C-12=-OH
B C-12=-H
A and C
A C-3"=OCH3
C C-3"=-OH
O
OOH
HO
O
O O
N
HO
O
OHOMeO
HO
Erythromycin A
1
69
312
3"1"
1'3'
Cladinose
Desosamine
Erythronolide A
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Extremely unstable under acid condition
O
O
OH
O
OHO
OO
OH
OHO
O
NOH
O
O
OHO
OO
OH
OHO
O
NOHO
O
O
OHO
OO
OHO
O
N
OO
HO
O
OO
HOO
N
OO
OH
OHO
OOH
+
1. H+
2. - H2O
ÍÑË®Îï8,9-Anhydroerythromycin A -6,9-hemiketal
ÂÝÐýͪAnhydroerythromycin A -6,9-9,12-spiroketal
¿ËÀ ¶¨ ÌÇCladinose
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Simply modification of erythromycin-Ester Pro-drug
O
O
OH
O
OHO
OO
OH
ORO
O
NOH
ºì ùËØ̼ËáÒÒõ¥Ery thromy cin Ethy lcarbonate R = -COOCH2CH3ºì ùËØÓ²Ö¬Ëáõ¥Ery thromy cin Stearate R = -CO(CH2)16CH3çúÒÒºì ùËØEry thromy cin Ethy lsuccinate R = -CO(CH2)2OCOCH2CH3ÒÀÍкì ùËØEry thromy cin Estolate R = -COOCH2CH3, C12H25SO3H
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Strategy for erythromycin modification
O
O
O
O O
O
HOOH
OHOMe
HO
NMe2
HO
OH
Alkylation of hydroxylgroup
Replacement of hydrogen
Conversion to aminesConversion to oximeRing expansion
Conversion to 11,12-cyclicderivatives
Cut Cladinoseto ketolides
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°¢ÆëùËØ¡¡ Azithromycin
Dirithromycin
Erythromycin Oxime
ÂÞºì ùËØ¡¡ Roxithromycin
¼×»ù»¯»¹Ô
BeckmannRearraangement
O
N
OH
O
OHO
OO
OH
O HO O
N
O
OO
O
OH
O
OHO
OO
OH
OHO O
NOH
N
O
OH
O
OHO
OO
OH
OHO O
NOH
HN
O
OH
O
OHO
OO
OH
OHO O
NOH
HNO
O
N
OH
O
OHO
OO
OH
O HO O
NOH
O OO
O
O
OH
O
OHO
OO
OH
O HO O
NOH
O
N
OH
O
OHO
OO
OH
O HO O
NOH
OH
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Erythromycin derivatives
O
OH
O
OHO
OO
OH
OHO
O
NOH
O F
O
O
O
OHO
OO
OH
OHO
O
NOH
O
·úºì ùËØFlunithromycin
¿ËÀ ùËØClarithromycin
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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.
O
O
O
O ONOMe
HO
NMe2
O
O
O
N
N
N
Telithromycin
1
3
69
1112
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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 gr
oup (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
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Chloramphenicol Antibiotics
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Chloramphenicol ( 氯霉素 )
O2N
OH
H
H
HO
HN
Cl
Cl
HO
Chemical name:
D-(-)-threo-1-p-nitrophenyl-2-dichloroacetamido-
1,3-propanediol
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A molecule, with two chiral centers, has four iso
mers (diastereomers). CHO
H OH
CH2OH
H OH
³àÞºÌÇD-(-)-erythrose
CHO
HO H
CH2OH
H OH
ËÕ°¢ÌÇD-(-)-threose
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1R, 2R (-) 1S, 2S (+) 1S, 2R (+) 1R, 2S (+)
D-(-)-Threo ¡¡ ¡¡ ¡¡ ¡¡ L-(+)-Threo ¡¡ d-(+)-Erythro¡¡ ¡¡ ¡¡ ¡¡ ¡¡ ¡¡ L-(-)-Erythro
NO2
C1
C2
CH2OH
HHO
NHCOCHCl2H
NO2
C1
C2
CH2OH
OHH
HCl2CHCOHN
NO2
C1
C2
CH2OH
OHH
NHCOCHCl2H
NO2
C1
C2
CH2OH
HHO
HCl2CHCOHN
Chloramphenicol is an antibiotic produced by Streptomyce
s venezuelae and other soil bacteria that was first discover
ed 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.
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Chemical properties
O2N
OH
H
H
OH
HN
OCl
Cl
HHN
OH
H
H
OH
NH
OCl
Cl
H
HO
OH
H
H
OH
NH
OCl
Cl
H
N
HOO
Zn, HCl
O
Cl
FeCl3
ôÇ°· ÑÜÉúÎïChloramphenicol Hydroxyamine
OH
H
H
OH
NH
OCl
Cl
H
N
HOO
3
Fe
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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.
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Usage
Despite potentially serious limitations, Chloramphenicol is an excellent drug when used carefully. Its special value is in typhoid ( 伤寒 ) and paratyphoid fever (副伤寒) , Haemophilus infection , pneumococcal ( 肺炎球菌 ) and meningococcal meningitis( 脑膜炎 ) in β-lactam allergic patients, anaerobic( 厌氧菌 ) infection , rickettsial infections, and so on.
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Synthesis O2N
O
Br2, C6H5ClO2N
O
(CH2)6N4, C6H5ClO2N
O
.(CH2)6N4
C2H5OH,HCl, H2OO2N
O
NH2.HCl
Br Br
Ac2O, AcONaO2N
O
NH
O
p-Nitro- -aminophenylacetone
HCHO, C2H5OH
pH = 2~7.5
O2N
O
NH
OHO
HAl[OCH(CH3)2]3, HOCH(CH3)2
O2N
NH
OHO
H
H OH
HCl, H2OO2N
NH2
HO
H
H OH
.HCl
15% NaOH O2N
NH2
HO
H
H OH
Resolution
O2N
OH
H OH
NH2H Cl2CHCOOCH3, CH3OH
O2N
OH
H OH
H HNCl
Cl
HO
p-Nitro- -acetamido- -hydroxyphenylpropanone ( )-thero-1-p-nitrophenyl-2-acetamidopropane-1,3-diol±
( )-thero-1-p-nitrophenyl-2-aminopropane-1,3-diol±
D-(-)-thero-1-p-nitrophenyl-2-aminopropane-1,3-diol
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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.
Chloramphenicol Palmitate ( 棕榈氯霉素 )
OH
H
H
O
NH
OCl
Cl
H
O
O2N
×ØéµÂÈùËØChloramphenicol Palmitate
C15H31-
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Chloramphenicol Sodium Succinate ( 琥珀氯霉素钠 )
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%.
OH
H
H
O
NH
OCl
Cl
H
OH
O
OO2N
çúçêÂÈùËØChloramphenicol Succinate
Na
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Summary
Tetracyclines Aminoglycosides Macrolides
Erythromycin Structure modification of
semi-synthetic erythromycin
Chloramphenicol Mechanism of action
O
O
OH
O
OHO
OO
OH
OHO
O
NOH
OH
O2N
HOH
HHN
O
Cl
Cl
H
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Question: 1. Why is the erythromycin A unstable in acidic co
ndition? 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 药物化学学习指导 , 第八章