ANTIBIOTICS

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ANTIBIOTICS

• Classification according chemical structure
  similarity
• I. ß-Lactam antibiotcs
• II . The Aminoglycoside Antibiotics
• III . The Macrolide Antibiotics
• IV Antibiotics with fused ring systems
• V. Lincomycins
• VI. Polyenes Antibiotics (Antifungal Antibiotics)
• VII .Polypeptide Antibiotics
• VIII.Unclassified antibiotics

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A. Penicillin

• Natural penicillin
• Penicillin G benzylpenicillin
• ß-Lactam thiazolidine penam penicillin
  penicillanic acid

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Semisynthetic Penicillins

• When creating the semisynthetic Penicillin, the
  task was posed of producing drugs
• 1-Not sensitive to the action of Penicillinase,
  (the latter is produced by a number of bacteria)
  because it decomposes, i.e. inactivates
  penicillin.
• 2-Resistant to acids
• 3- having a broader spectrum of action than
  benzyl penicillin.

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Structure Activity Relationships

• 1-Substitution of an electron withdrawing group
  at Alfa position of the acyl carbon stabilize
  the penicillin to acid-catalyzed hydrolysis e.g..
  Penicillin V and ampicillin, the increased
  stability has been attributed to a decrease in
  reactivity (nucleophilicty) of the side chain
  amide carbonyl oxygen toward participation in
  ßlactam ring opening to form penicillenic acid.

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• Penicillin V Phenoxymethyl penicillin
• is an acid-stable penicillin given by mouth.
• It is used mainly in the treatment of
  streptococcal
• infections and in rheumatic fever prophylaxis

PHENETHICILLIN
Penicillin V
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• 2-It was found that increasing the steric
  hindrance at the a-carbon of the acyl group
  increased resistance to staphylococcal
  ß-lactamase, with maximal resistance being
  observed with quaternary substitution. The bulky
  group interfere with the enzyme attachment to the
  penicillin and causes conformational change in
  the enzyme and loss of activity.

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Cloxacillin sodium
3-(0-chlorophenyl)-5-methyl-4- isoxazolyl
penicillin
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• 3- The introduction of an ionized or polar group
  into the a-position of the side chain benzyl
  carbon atom of penicillin G confers activity
  against gram-negative bacilli. Hence, derivatives
  with an ionized a-amino group, such as ampicillin
  and amoxicillin, are generally effective against
  such gram ve genera This selective penetration
  is believed to take place through the porin
  channels of the cell membrane

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• Ampicillin
• 6-D-a-Aminophenylacetamido penicillanic acid
  6--amino-benzyl penicillin

Amoxicillin, 6-D-(-)--Amino-p-hydroxy-phenylacet
amido penicillanic acid (Amoxil).
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• 4-The incorporation of an acidic substiuent at
  the a-benzyl carbon atom of penicillin G also
  imparts clinical effectiveness against
  gram-negative bacilli and, furthermore, extends
  the spectrum of activity to include organisms
  that are resistant to ampicillin .

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Carbenicillin Disodium
Disodium a-carboxybenzyl penicillin . Its
structure shows that it differ from ampicillin
by having an ionizable carboxyl group
Ticarcillin Disodium, USP. a-Carboxy-3-thienylpen
icillin (Ticar) is an isostere of carbenicillin,
wherein the phenyl group is replaced by a
thienyl group. This semisynthetic penicillin
derivative as with carbenicillin,
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Salts of Penicillin

• Penicillin G procaine

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penicillin G benzathine
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Mode of action of penicillin

• .
• Inhibit cell wall synthesis by acylation of
  transpeptidase enzyme necessary for synthesis of
  dipeptidogycan which responsible for rigidity and
  strength of the cell wall

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Allergy to Penicillins

• Allergic reactions to various penicillin,
  ranging in severity from a variety of skin and
  mucous membrane rashes to drug fever and
  anaphylaxis, constitute the major problem
  associated with the use of penicillin.
• Evidence suggests that penicillin, or their
  rearrangement products formed in vivo (e.g.,
  penicillenic acids) react with lysine-e-amino
  group of proteins to form penicilloyl protein,
  which are major antigenic determinants. Clinical
  observations indicated a higher incidence of
  allergic reaction with unpurified amorphous
  preparations, compared with highly purified
  crystalline forms and with polymeric impurities
  in ampicillin dosage

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Potency

• The initially used penicillin was not pure
  compound exhibiting varying activity, therefore
  it was necessary to evaluate it by
  microbiological mean and the value become known
  as oxford unit the smallest amount of penicillin
  that will inhibit in vitro the growth of a strain
  of staph in 50ml culture media under specified
  condition now, pure crystalline penicillin is
  available, the USP defines the unit as the
  antibiotic activity of 0.6ug of USP penicillin G
  sod reference standard
• The weight-unit relationship of the penicillin
  will vary with the nature of the acyl substituent
  and with the salt formed with free acid

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Methods of quantitative analysis

• .
• 1-Iodimetrical determination of the penicillin
  after the drugs have been hydrolyzed with an
  alkali (for all penicillin drugs). Since
  penicillin itself is not oxidized by iodine, but
  the products of its alkaline hydrolysis are
  oxidized penaldic acid and penicillamine, are
  oxidized by an iodine solution added to the
  reaction

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• 2. Gravimetry Benzylpenicillin in drugs
  containing its potassium, sodium, and procaine
  salts is determined by the gravimetric method
  based on the formation of the N-ethylpiperidine
  salt of benzyl penicillin (the gravimetric form)
• 3. Colorimetry Ampicillin decompose at pH 5.3
  for 30 min at 75C in the presence of copper
  sulphate. Under these conditions ampicillin
  decomposes and rearranges to a-aminobenzyl
  penillic acid, which is estimated colorimetry.

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ß-Lactamase inhibitors

• Clavulanate Potassium.
• Clavulanic acid is an antibiotic isolated from
  Streptomyces clavuligeris. Structurally it is
  1-oxapenam lacking the 6-acylamino side chain of
  penicillin, but possessing a 2-hydroxyethylidene
  moiety at C-2.

very weak antibacterial activity
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Sulbactam

• Penicillanic acid sulfone or 1,
  1-dioxopenicillanic acid.
• This synthetic penicillin derivative is a potent
  inhibitor of ß-lactamase. it potentiates the
  activity of ampicillin and carbenicillin against
  ß -lactamase producing bacteria.

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• Combinations of amoxicillin and the potassium
  salt of clavulanic acid are available (Augmentin)
  in a variety of fixed-dose, oral dosage forms
  intended for the treatment of skin, respiratory,
  ear and urinary tract infections caused by
  b-lactamase producing bacterial strains resistant
  to amoxicillin alone.

Combinations of ampicillin and sulbactam are
marketed under trade name Unasyn for the
treatment of skin tissue, and gynecologic
infections.
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B- Cephalosporins

• Cephalosporins are ß-actam antibiotics isolated
  from cephalosporium
• species or prepared semisynthetically

Semisynthetic Derivatives In the preparation of
semisynthetic cephalosporins, the following
improvements are sought (1) increased acid
stability (2) improved pharmacokinetic
properties, particularly better oral absorption
(3) broadened antimicrobial spectrum (4)
increased activity against resistant
microorganisms. (5) decreased allergenicity and
(6) increased tolerance after parenteral
administration
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Oral cephalosporins

• The oral activity conferred by the phenylglycyl
  substituent is attributed to increased acid
  stability of the lactam ring resulting from the
  presence of a protonated amino group on the
  7-acyl amino portion of the molecule.
• cephaloglycin, is poorly absorbed orally
• Cephem

CH2OCOCH3
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• presumably because of solvolysis of the 3-acetoxy
  group in the low pH of the stomach. The resulting
  3-hydroxyl methyl derivative is known to under go
  lactonization under acidic conditions

Cephalexin (Keflex) For urinary and upper
respiratory tract infection
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Cephradine, USP (Velosef) Available oral and
parentral
Cefadroxil, USP (Duricef ) Slowly excreted ,
longer duration of action
Cafaclor USP (Ceclor) More potent against
homophiles influenza
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Parental Cephalosporins

• Hydrolysis of the ester function, catalyzed by
  hepatic and renal esterases, is responsible for
  some in vivo inactivation of parenteral
  cephalosporins containing a 3-acetoxymethyl
  substituent (e.g.cephalothin and cefotaxime).

Cephalothin Sodium (Keflin
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a second - generation
cephamycins It is a semisynthetic derivative
7a-methoxy-substituted cephalosporin Cefoxitin
Sodium, (Mefoxin).
Cefamandole Nafate (Mandol
formate ester of cefamandol
Parenteral cephalosporin lacking a hydrolysable
group at the 3-position e.g. cephamandole not
subject to hydrolysis by esterase's.
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Third-generation cephalosporin Wider spectrum of
activity meningitis
Cefotaxime Sodium (Claforan)
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• Fourth generation cephalosporin
• Cefepim
• Cefpirome
• R

                                               
                                                  
 
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II . Aminoglycoside Antibiotics

• Aminologlycosides are so named because their
  structures consist of amino sugars linked
  glycosidically.
• The streptomycin, neomycin, paromomycins,
  gentamicins, Tobramycins, Kanamycins, and
  Amikacins
• have many chemical and antimicrobial features in
  common
• All these antibiotics show broad spectrum
  antimicrobial activity, and paromomycin also
  inhibits Enatmoeba histolytica.
• None of the aminoglycoside antibiotics is
  absorbed from the alimentary tract, and neomycin
  has been used widely in the treatment of
  intestinal infections and chemosterilization of
  the bowel prior to surgery of that organ

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• All have at least one aminohexose and some have a
  pentose lacking an amino group (e.g..
  streptomycin) additionally,
• each contains a substituted 1,3 -
  diaminocyclohexane central ring
• in Kanamycin, neomycin, gentamicin, and
  tobramycin it is deoxystreptamine,
• and in streptomycin it is 1,3 -
  diguanidocyclohexane streptadine

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Mechanism of Action

• The amino glycosides act directly on the
  bacterial ribosome to inhibit the initiation of
  protein synthesis and to interfere with the
  fidelity of translation of the genetic message.
  They bind to the 30 S ribosomal subunit to form a
  complex that is unable to initiate proper amino
  acid polymerization

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Streptomycin
. It was shown eventually to be composed of three
glycosidcally linked units streptidine,
streptose and N-methyl-L-glucosamine.
Showed marked activity against Gram-positive and
gram-negative bacteria as well as particular
effectiveness against Mycobacterium
tuberculosis.
In the presence of dilute aqueous alkali
streptomycin undergoes a degradative
transformation to give gamma- pyrone,
maltol. The maltol is derived from the streptose
portion of the molecule it can be readily
estimated calorimetrically
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Amikacin (Amikin)

• 1-N- Amino - hydroxybutyryl Kanamycin.

A semi synthetic amino glycoside by acylation of
the 1-amino group of the deoxystreptamine ring
of kanamycin A with L amino- hydroxybutyric
acid. Active against gram negative bacteria
given im or iv not absorbed by mouth.
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III . Macrolide Antibiotics

• Macrolides are a group of macrocyclic
  antibiotics containing
• a large non-planar strain less lactone ring
  (12-16 atoms)
• An amino sugar linked glycosidically to the
  lactone ring,
• A neutral sugar linked to the ring or the basic
  sugar
• and contains a ketone group.
• Hydrolysis of the glycosidic bonds takes place in
  acid solutions ,saponification of the lacton
  ring in basic-media.
• The macrolides are principally active against
  Gram positive bacteria and show useful activity
  against penicillin-resistant strains. Also
  exhibit effectiveness against gram-negative
  cocci.

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Mode of action

• Bacteriostatic ,bind to 50 S ribosomal subunit
  to prevent the translocation step
• of bacterial protein synthesis

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Erythromycin (Erythrocin)

• Erythromycin on hydrolysis provides
• a neutral sugar cladinose
• Desosamine (a basic sugar)
• and the aglycone,
• erythronolide.
• Clarithromycin semisynthetic
• erythromycin
• OH at C6 converted to methyl ether

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Oleandomycin
Most of th
Most of th

• Oleandolide is a 14-atom
• ring that contains an exocyclic
• methylene epoxide on carbon 8

Semisynthetic oleondomycin triacetyl derivative.
(TAO) troleandomycin
A combination of oleandomycin with
tetracyclines, on the basis that it provides a
synergistic effect and provides protection
against resistant micro organisms (sigmamycin).
e
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Spiramycin (Rovamycin)

• Spiramycin is a macrolide antibiotic produced by
  the growth of certain strains of streptomyces
  ambofaciens which has been used similarly to
  erythromycin. It has also been used to treat
  protozoal infections and toxoplasmosis.

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Azithromycin

• Semi synthetic erythromycin with ring
  enlargement by introduction of N-CH3 between C9
  and C10.
• It has the following advantages
• More stable to acid degradation
• Longer half life once a day dosage
• More potent against gm -ve

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IV Antibiotics with fused ring systems

• The group includes the broad-spectrum
  tetracycline.
• The Tetracycline
• Comprises a group of antibiotics characterized by
  their common octahydronaphthacene
• skeleton.

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Mode of actioninhibit bacterial protein
synthesisbind with 30S ribosomal
subunitchelating agent
Epimerization. Dimethyl amino inverted from to
ß Salt of tetracycline Action of acid and
alkali contraindication
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Other names Achromycin oxycycline Terramycin Demeclocycl Methacycline Doxycycline Minocycline R4 H Cl H Cl H H N(CH3)2 R3 CH3 CH3 CH3 H CH3 H R2 OH OH OH OH CH2 H H R1 H H OH H OH OH H Name a. Tetracycline b. 7-Chlortetracyclin c. 5-Oxytetracyclin d.6-Demethyl-7-chloro tetracycline e 6-Demethy1-6-deoxy-5-hydroxy-6-methylene tetracycline f. 6-Deoxy-5-oxytetracycline g. 7-Dimethylamino 6-demethyl-6-deoxytetracycline
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Rolitetracycline
Rolitetracycline is a tetracycline derivative
with general properties similar to those of
tetracycline . It is included in some topical eye
preparations. It has also been given by
injection Synthesis

Mannich Ter.butyl alc. HCHO PYRROLIDINE
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V. Lincomycins

• They are known as Sulphur containing Antibiotics,
  
• act via 50S ribosomal subunit binding protein
  synthesis inhibition.They are used in extra CNS
  anaerobic infections, Penicillin sensitive
  patients

LINCOMYCIN natural
CLINDAMYCIN semi synthetic
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CLINDAMYCIN

• semi synthetic lincomycin
• By reaction of lincomycin with thionyl chloride
  SOCl2
• Replacement of OH by Cl with inversion of
  configuration
• 7S-Cloro-7S-deoxylincomycin
• More lipophilic
• Inhanced antibacterial activity

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VI Polypeptide Antibiotics

• The most powerful antibiotic agents but limited
  for renal toxicity.
• Used mainly locally in burns.
• Inhibit mucopeptide cell wall synthesis and
  interfere with semipermeability of cell membrane

BACITRACIN G ve few g -ve
GRAMICIDIN G ve
POLYMYXIN (B) Avtive against g -ve
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VII.Polyene antibiotics (antifungal)common
characters

• Macro cyclic lacton 38 atoms
• Conjugated polyenes
• amphoteric

AMPHOTERICIN (B)
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Mode of action Inhibit cell membrane
synthesis, alter cell permeability, form complex
with ergosterol of fungi
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VIII. Unclassified Antibiotics

• CHLORAMPHENICOL
• In meningitis, typhoid paratyphoid fever.

D-(-) threo-2-Dichloroacetamido
--1-(4nitrophenyl)-1,3-propanediol
Thiamphenicol CH3SO2-
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• Mode of action
• Bacteriostatic inhibit bacterial protein
  synthesis
• Assay
• Diazometric after reduction of nitro group
• Metabolism
• O-Glucuronoid
• Reduction NO2
• Acylation OH