Antibiotics

1
ANTIBIOTICS
Presanted by
K. Madhavi, Assistant Professor,
department of pharmaceutical
Chemistry.

 ANTIBIOTICS
 Classification
 BETA-LACTAM ANTIBIOTICS
• Introduction
• Classification
 PENCILLINS
• Introduction and nomenclature
• Classification
• Structural Activity Relationship
• Mechanism of Action
 CEPHALOSPORINS
• Introduction
• Classification
• Mechanism of Action
• Clinical uses
 Key points
 Conclcsion
2

 Antibiotics are the chemical substances produced by
various species of micro organisms and other living
systems which in small concentration kill or inhibit the
growth of other micro organisms.
Classification
β- Lactam antibiotics
Monobactams
Aminoglycosides
Tetracyclines
Macrolides
Lincomycins
Polypeptides
3

 The name “Lactam” is given to cyclic amides and is analogous to
the name “Lactone” which is given to cyclic esters .
 Antibiotics that contains the β-lactam (a four membered cyclic
amide) ring structure constitute the dominant class of agent
currently employed for the chemotherapy of bacterial infections.
 β-lactam are the most widely used group of antibiotics available.
4
INTRODUCTION

CLASSFICATION OF β-LACTAM ANTIBIOTICS
5

1
• Beta Lactam antibiotics are indicated for the prophylaxis
and treatment of bacterial infections caused by
susceptible organisms.
2
• Traditionally Beta Lactam antibiotics were mainly active
only against gram positive bacteria
3
• The beta lactam antibiotics active against various gram
negative organisms has increased their usefulness
6
CLINICAL USES

7
ADVERSE
EFFECTS
fever
angioedema
nausea
dermatitis
erythema
rashes
diarrhea
vomiting

PENICILLINS:
 It is an antibiotic, discovered by Alexander
Fleming(1881-1955) in 1928.
 β-lactam antibiotics
 It was isolated from fungus
Penicillium notatum.
9
Alexander Fleming
(Penicillium notatum)

 Florey and Chain isolated penicillin by
freeze drying and chromatography.
 Penicillin was effective even when it is
diluted up to 800 times.
Biological sources:
Penicillium notatum, Penicillium chrysogenum
10
Fleming’s famous petridish
Penicillium chrysogenum

BASIC STRUCTURE OF PENICILLIN:
11
Acyl amino side chain
6-Amino
penicillanic
acid
H
C
C N
H
C
C
C
S
O
CH3
CH3
COO-
H
HNCR
O
Free carboxylate
Cis stereochemistry
Most reactive carbonyl group
Site of Penicillinase action
Basic chemistry:Beta lactum ring+Thiazolidine ring
Bicyclic ring system sysyem is essential
Variable group
Beta lactum ring
Thiazolidine ring
Methyl groups

12
N
S
O
Penam
CA-
system
USP-System
4-thia-1-aza bIcyclo[3.2.0]-7-
heptone
1-thia-4-aza bicyclo[3.2.0]-7-heptone
N
S
NH
COOH
O
COR
1
2
34
56
7
According to chemical abstract naming starts
from sculpture atom and is called 6-acyl amino
-2,2-dimethyl penam 3-carboxylic acid
But in USP naming starts from nitrogen atom
6-acyl amino -3,3-dimethyl penam 2-carboxylic
acid
NOMENCLATURE
N
S
COOH
O
Penicillanic Acid

Classification of Penicillins
Natural penicillins β- lactamase resistant
penicillins
Aminopenicillins Carboxypenicillins Ureidopenicillins
-Penicillin G
-Penicillin V
-Methicillin
-Nafacillin
-Isoxazolyl Penicillins
-Ampicillin
-Amoxicillin
-Ticarcillin -Piperacillin
-Mezlocillin
-Azlocillin
14

PENICILLIN G (BENZYL PENICILLIN)
 Acid unstable.
 Parenteral route.
 Self destructive mechanism in its
structure because of influence of acyl side chain.
17
N
S
CH3
CH3
COOH
O
HNCH2C
O
H H
H
PENICILLIN DERIVATIVES

PENICILLIN V
 More acid stable than Penicillin G.
 Administered by oral route.
 Electron withdrawing group is present in
acyl side chain.
18
N
S
CH3
CH3
COOH
O
HNCH2C
O
O
H H

METHICILLIN:
 Has no electron withdrawing group
on the side chain.
 Acid sensitive and has to be injected.
 Steric shields can be added to penicillins to
protect from penicillinase enzyme.
19
N
S
CH3
CH3
COOH
O
HNC
O
H H
H
CH3
CH3

O
N
SNH
COOH
CH3
CH3
C
O
ISOXAZOLYL PENICILLINS
O
N
CH3
R1
R2
R1 R2
Oxacillin H H
Cloxacillin Cl H
Dicloxacillin Cl Cl
Better penicillinase resistant agents have been
developed.
The isoxazolyl ring acts as the steric shield but
It is also electron-withdrawing giving the
Structure acid stability.
Flucloxacillin Cl F
Bulky and electron
withdrawing
20

AMPICILLIN:
 If hydrophilic groups like
(NH2, OH , COOH ) are attached
to the carbon that is α to the carbonyl group
on the side chain then α hydrophilic group aids
the passage of penicillins through porins of gram –ve bacteria.
 Acid stable
21
N
S
CH3
CH3
COOH
O
HNC
H H
HC
O
H
NH2

AMOXICILLIN:
 β hydroxy ampicillin.
 Same spectrum of activity as that of penicillin G but more
active against gram–ve bacteria.
 Acid resistant hence given orally.
 Non toxic.
22
N
S
CH3
CH3
COOH
O
HNC
H H
HC
O
H
NH2
HO

24
STRUCTURALACTIVITY RELATIONSHIP :
1
2
3
4
56
7

Bacteristatic
Antibiotics
Bactericidal
Penicillins
Inhibit the synthesis of peptidoglycon layer containing NAM &NAG
connected by penicillin binding proteins(PBP)
Acts on PBP and inhibits the synthesis of Peptidoglycon.
25
MECHANISM OF ACTION:
Gram +ve Gram -ve
Cell membrane
Peptidoglycon
cell wall
Lipopolysacc
haride layer

(Peptidoglycan cell wall)
N-acetylglucosamine
N-acetylmuramic acid
Transpeptidases located
within the cell membrane
are responsible for
cross linking the
Peptidoglycan chains
Transpeptidases
(Penicillin Binding Proteins)
In order to make the rigid grid,
There is an enzyme called
Transpeptidase,which connects
the Little peptide strings
perpendicular to the NAM and
NAG chains.
Cell membrane
26

(Cell membrane)
(Peptidoglycan cell wall)
Penicillin’s inactivate
the transpeptidase enzyme
by covalently bonding
to the serine residues
within the active site.
Bonding is by acetylation
Transpeptidases
(Penicillin Binding Proteins)
S
O
27

BETA LACTAMASE INHIBITORS:
 Has negligible antibacterial activity.
 Given with Penicillins which increases spectrum of activity.
 Microbial resistance to beta lactam antibiotics.
28
Beta lactamase

β lactam antibiotics β lactam antibiotics + β lactamase inhibitor
Contain β lactum ring Complex
Catalysing the
β lactamases hydrolysis of
β lactum ring Effectiveness of β lactamase is diminished
INACTIVE COMPOUNDS
Enhances the activity of β lactam
antibiotics
29

Clavulanic acid:
 Isolated from Streptomyces clavuligerus.
 1st naturally occurring β lactam ring that was not fused to a ‘S’
containing ring.
Sulbactum:
 β lactamase disabiling agent.
 Prepared by partial chemical synthesis
from penicillins.
30
N
O
O
H
COOH
H
H
OH
N
S
O COO-
Na+
H
O
CH3
CH3
O
H

Tazobactum:
 Co-administered with Piperacillin.
 Has little or no antibacterial activity.
31
N
S
O COO-
O CH3
O
H
N
N
N
Beta lactamase Inhibitors:
Available agents β-lactamase binding Potency
Clavulanic acid + + + + + +
Sulbactam + + + + + +
Tazobactam + + + + + + + +

USES:
 Streptococcal infections
 Pneumococcal infections
 Meningococcal infections
 Gonorrhoea
 Syphilis
 Diphtheria
 Tetanus
TOXICITY:
 Nausea ,Dizziness ,Head ache ,skin rashes ,Bronchospasm ,
vasculitis , inflammation of blood vessles .
 Hypersensitivity or allergic reactions. 32

Cephalosporins are second major group of β-lactam ,broad
spectrum,penicillanase resistant antibiotics
 They were isolated from cultures of
Cephalosporium acremonium by italian scientist
Giuseppe Brotzu in 1945.
34
INTRODUCTION

 In 1948, Abraham and his colleagues have isolated three principle
antibiotic components from cultures of fungus.
 1964 ,the first semi synthetic cephalosporin i.e. cefalothin was
launched in the Market by Eli Lilly and company.
35
Cephalosporin P
Cephalosporin N
Cephalosporin C

CLASSFICATION OF CEPHALOSPORINS
First
Generation
Second
Generation
Third
Generation
Fourth
Generation
Fifth
Generation
1.Parenteral 1.Parenteral 1.Parenteral 1.Parenteral 1.Parenteral
Cephalothin Cefamycinc Cefotaxime Cefepime Ceftobiprole
Cephaloridine Cefoxitin Ceftazidime Cefpirome
Cefazolin Cefotitan Ceftriaxone
Cefmetazole
2.Oral 2.Oral 2.Oral
Cephalexin Cefachlor Cefixime
(Keflex) Cefprozil Cefdinir
Cephadroxil Ceftibuten
(Durecef)
3.Oral & Parenteral 3.Oral & Parenteral
Cephradine cefuroxime acetil
36

37
 These drugs are very active against Gram-positive cocci (such as
Pneumococci, Streptococci, and Staphylococci).
 They do not cross BBB.
1ST Generation Cephalosporins:

38
They have a greater gram-negative spectrum while retaining some activity
against gram-positive bacteria.
 They are also more resistant to β-lactamase.
No BBB Penetration.
2nd Generation Cephalosporins:

39
Expanded Gram-negative coverage
 Able to cross the BBB.
Anti-pseudomonal activity.
3rd Generation Cephalosporins:

40
 Zwitterionic compounds.
 Good affinity for the transpeptidase enzyme.
 Low affinity for some β-lactamases.
 Cross BBB and effective in meningitis.
4th Generation Cephalosporins:

41
CEFTOBIPROLE
 Active against
methicillin-resistant -Staphylococcus aureus
penicillin-resistant - Streptococcus pneumoniae
5th Generation Cephalosporins:

STRUCTURE -ACTIVITY RELATIONSHIP:
42
Basic chemistry:β-lactam ring+Dihydrothiazine ring
Variable group
Variable group7-Aminocephalosporanic acid

45
Cephalosporins are bactericidal.
Cephalosporins and β-lactams bind to
PBPs(Penicillin Binding Proteins).
Some PBPs have transpeptidase
activity.
Transpeptidase activity is essential
in cell wall synthesis.
MECHANISM OF ACTION:

USES:
46
Adverse effects:
Disulfiram- like effect
Nephrotoxicity
Bleeding
Allergic reactions
Phlebitis
IMPETIGO CELLULITIS P.aeruginosaINFECTIONS
PNEUMONIA BACTERIAL MENINGITIS

Cephalosporins advantages over penicillins:
 Increased acid stability compare to penicillins.
 Most of the drugs have better absorption than penicillins.
 Broad antimicrobial spectrum.
 Increased activity against resistant microorganisms.
 Decreased allergenicity.
 Increased tolerence than penicillins.
48

 Carbapenems are a class of β-lactam antibiotics with a broad spectrum
of antibacterial activity.
 They have a structure that renders them highly resistant to most
β-lactamases.
 Carbapenem antibiotics were originally developed from the carbapenem
thienamycin, a naturally derived product of Streptomyces cattleya
Examples
Imipenem, Meropenem, Ertapenem
49
INTRODUCTION

IMIPENEM:
 IMIPENEM has a wide spectrum with
good activity many gram negative rods
incluiding P.aeruginosa, gram positive organisms and anaerobes.
 Imipenem is inactivated by dehydropeptidases in renal tubules,
result in low urinary concentrations.
50
(Imipenem)

Carbapenems which tend to be more common with imipenem are nausea,
vomiting, diarrhea, skin rashes, and reactions at the infusion sites
Excessive levels of imipenem in patients with renal failure may lead to
seizures
Patients allergic to penicillins may be allergic to carbapenems.
51
ADVERSE EFFECTS

KEYPOINTS:
 Penicillins have a bicyclic structure consisting of a β-lactam
ring fused to a Thiazolidine ring.
 Penicillin can be made more resistant to acid conditions by
incorporating an electron withdrawing group into the acyl
side chain.
 Broad spectrum activity is associated with the presence of an
α-hydrophilic group on the acyl side chain of penicillins.
 Cephalosporins contain a strained β-lactam ring fused to a
dihydrothiazine ring.
 Semi-synthetic cephalosporins can be prepared from
7- aminocephalosporanic acid.
 Methyl substitution at the 3-position of cephalosporins is
good for oral absorption.
52

 Beta lactam antibiotics are useful and frequently prescribed
antibiotics that share a common structure.
 Bacterial resistance against the beta lactam antibiotics continues
to increase at a dramatic rate.
 Therapy with beta lactam antibiotics is a dynamic that
prevalence of bacterial resistance to these agents continues to
rise, while new and more effective agent are released for clinical
use.
53
Conclusion:

 William O. Foye.,Textbook of Medicinal Chemistry,Pg no: 1089 -1106
 Sriram., Medicinal Chemistry, Pg no: 295-309.
 Kadam., Textbook of Medicinal Chemistry, Pg no: 68-82.
 Ilango., Principles of Medicinal chemistry(vol.1), Pg no: 121-143.
 G.L.Patrick., Introduction to Medicinal Chemistry, Pg no:388-415.
 Good man And Gil Man’s ;The Pharmacology Basis Of Therapeutics
Tenth Edition page no 1189-1225.
 JH Block & JM Beale., Wilson & Giswold’s Textbook of Organic
Medicinal Chemistry & pharmaceutical chemistry 11th Edition, 2004.
54
Reference:

CONTENTS
1. Definition
2. Introduction
3. Classification
4. Sources
5. Chemistry
6. SAR of tetracyclines
7. Mechanism of action of tetracyclines
8. Spectram activity
9. Uses of tetracyclines
10. Side effects of tetracyclines
56

57
TETRACYCLINES
 Tetra means = Four
 Cycl means = Hyrocarbon ring
 Ine means = Derivation

Tetracyclines are introduced 50 years ago as potent broad spectrum
antibiotics.
They are biosynthesized from acetic acid and propionic acid units in
microorganisms.
Tetracyclines possess a wide specturm of acitivty i.e. gram+ve and gram-ve
bacteria.
They are mainly designed for oral route but parenteral and topical forms are
available.
58

Tetracyclines are obtained from various
species of Streptomyces bacteria by
fermentation technology
Chlortetracycline(aureomycin)
from Streptomyces aureofaciens.
Oxytetracycline (Terramycin)
from Streptomyces rimosus.
60

Stereochemistry of tetracyclines is very complex.
61
4,4a,5,5a,6,12a
Methacycline , Oxytetracycline, Meclocycline, Doxycycline
possess 5-hydroxy Substituent have 6 chiral carbon atoms.
Others have only 5 chiral carbon atoms.

Important structrual units and the three acidity constants in the
tetracycline molecule.
(conjugated
Trione system
Is acidic nature)
pka1 (2.8-3.4)
(Conjugated phenolic
Enone system is slightly
basic)
Strong alkaline.
Pka (7.2-7.8) Pka3 (9.1-9.7)
62

O O
OH
NH2
CH3HO
C
O
OH
OHOH
CH3H3C
N
H3C
CH3
H3C
H
N
O
N
H
CH3H3C
N
O O
OH
NH2
C
OH
OHOH
CH3H3C
N
O
CH3H3C
N
O O
OH
NH2
C
OH
OHOH
CH3H3C
N
O
O O
OH
NH2
C
OHCH2
O
OH
OHOH
CH3H3C
N
N
H3C CH3
OH OH
OH
O
OH
C
HO CH3
NH2
OH
OO
N
H3C CH3
Cl
OH OH
OH
O
CH2 OH
C
NH2
OH
OO
O O
OH
NH2
CH3HO
C
Cl
OOH
OH
OH
CH3H3C
N
O O
OH
NH2
H
C
Cl HO
OOH OH
OH
CH3H3C
N
121110
9
8
7
6
5
4
3
2
1
METHACYCLINE
[Rondomycin]
OXYTETRACYCLINE
Terramycin, (Urobiotic)
CHLORTETRACYCLINE
Aureomycin
TETRACYCLINE
Achrommycin, Sumycin,
Panmycin, Teracap, Tetracyn, Tetralan
TIGECYCLINE
Tygacil™
MECLOCYCLINE
Meclan
MINOCYCLINE
Arestin, Dynacin,
Vectrin, Minocin
DEMECLOTETRACYCLINE
Declomycin
O O
OH
NH2
C
H3C OHH
OOH OH
OH
CH3H3C
N
DOXYCYCLINE
Vibramycin, Vibra–Tabs
Doryx, Doxy
STRUCTURES OF IMPORTANT TETRACYCLINES
63

OH OH
CONH2
OH
R1
O O
R2
R3
H
R4
H
N(CH3)2
OH
ABCD
1
2
3
4
4a
5
5a
6
6a
7
8
9
10
10a
11
11a
12
12a
N(CH3)2 Increases
activity
Conversion to nitriles
causes a 20 fold increase
in activity
Modification leads
to loss of activity
=CH2 Increases the
Antibacterial activity
Elimination of 6-OH group
increase lipophilicity
& more stable to acids.
Ex: Doxycycline.
‘D’ ring should be
always aromatic
Changes in this ring
Leads to biological
inactivation of the
molecule.
Additional glycyl amino
substitution at the 9th
Position leads to the new
Class of antibiotics
the glycylcyclines.
EX: Tigecycline.(Tygacil)
The keto-enol
tatomerism
Between c2 and c3 are
very
important for
biological
activity.
Inviolate zone is essential
The linearly fused tetracyclic
nucleus is most important
for the antibiotic activity.
Electron donating (or)
electron withdrawing
groups at c7 increased
Antibacterial activity
Substitution with –OH Produce water
soluble derivatives which can
be administered orally.
Epimerization at c4
and dehydration at 5a
results loss of activity.
64
Structural Activity Relationship:

SUMMARY:
OH
CONH2
OHOH
R1
R2
O O
N(CH3)2
OH
H
R4
H
R3
1
4
2
3
4a
5
5a
6
6a
7
8
9
10
10a
11
11a
12
12a
ABCD
S.NO Structural Modifications Effects
1. Any modification No bacterial activity
2. Acetyl group only Slightly activity retained
3. Any modification No bacterial activity
4. α dimethylamino group NHCH3 retains more activity
5a. Loss of H Inactive degradation product
6. Remove OH,CH3 or both More stable compound
7. Cl,Br,NO2,(CH3)2N- Activity retained
8. Little information available _
9. Cl and CH3 Decreased activity
10,11,11a,12. “Inviolate zone” including C-1 Diminished activity

Epimerization:
OH
CONH2
OHOH
HO
O O
N(CH3)2
OH
H H
CH3
1
4
2
3
4a
5
5a
6
6a
7
8
9
10
10a
11
11a
12
12a
ABCD
H H
H
OH OH
CONH2
OH
O O
N(CH3)2CH3
H
H
H
OH
-H2O
Tetracycline
(Active)
Anhydrous Tetracycline
(Inactive)
H+
H
OH
CONH2
OH
OH O
H
H
H
OH
O
HO N(CH3)2
CH3 H
4-Epi tetracycline
(Inactive)
-H2O
H
OH OH
CONH2
OH
O O
CH3
OH
H
N(CH3)2
4-Epianhydro tetracycline
(Inactive)
H+
66
Strong acids and bases
Attack those tetracyclines
Which possess an –OH group at
C-6 and form inactive
anhydrotetracyclines

CHELATION:
Tetracyclines
Ca2+, Fe2+
Al3+, Fe3+
Citrates
lipoproteins
Serum albumin
globulins
Metal
complexes
(Insoluble in
water at
neutral PHs)
67
This insolubility is not only inconvenient for the preparation of
solutions but also interferes with blood levels on oral administration.
 The tetracycline's are incompatible with co-administered,
multivalent ion-rich antacids and with hematinics and concomitant
consumption of daily products rich in calcium ion also is
contraindicated.

Amphoteric nature of tetracyclines:
• Tetracyclines are amphoteric compounds.
• Amphoteric = form salts with both strong acids and bases.
Three structrual units of tetracyclines representing 3pka values.
 Pka1--- Conjugated trione system extending from C1 to C3 of
ring A is acidic nature of Pka 2.8-3.4.
 Pka2--- Conjugated phenolic enone system from C10-C12 is
associated with weak basic Pka values ranging from 7.2-7.8.
 Pka3-- C4 atom and its substituents exhibits Pka3 ranging from
9.1 to 9.7. which represents strong alkaline nature.
Because of the amphoteric nature tetracyclines forms water soluble salts
with strong acids such as HCl and strong bases such NaOH, KOH.
68

 Tetracyclines inhibit protein synthesis by binding to the bacterial ribosome involved
in the translation(protein synthesis) process and making them bacteriostatic.
 The bacterial ribosome is a 70s particle made up of 30s subunit and 50s subunit.
 The 30s subunit binds mRNA and initiates the protein synthesis.
 The 50s subunit combines with the 30s subunit-mRNA complex to form a ribisome
then binds aminoacyl tRNA and catalyses the building of the protein chain..
 There are two main binding sites for the tRNA molecule.
 The peptidyl(p-site) binds the tRNA bearing the peptide chain
 The acceptor aminoacyl site (A-site)
 Tetracyclines reversibly bind to the 30S subunit at the A-site to prevent attachment
of the amino acyl tRNA, terminating the translation process.
. .
69

Tetracycline is a bacteriostatic drug acts by binding reversibly to the 30S subunit of the bacterial
ribosome. This inhibits addition of amino acids to the growing peptide resulting in inhibition of
protein synthesis.
Site of action
70

 Gram +ve & -ve bacteria
 Spirochetes
 Mycoplasms
 Rickettsiae
 Candida Albicans
 Mycoplasma Pneumoniae
 Chlamydia Trachomatis
 Borrelia Recurrentis
 Yersinia Pestis
 Vibrio Cholerae
 Campylavacter Fetus
 Brucella Specie
 Streptococcus Pneumonia
 Neisseerie Gonorrhoeae
71
• Tetracyclines are broad spectrum antibiotics.
They are active against following micro organisms:

• Tetracyclines are called "broad-spectrum" antibiotics, because they can
be used to treat a wide variety of infections.
• Physicians may prescribe these drugs to treat eye infections.
• Tetracyclines are generally a low-cost alternative among antibiotics.
• Interestingly, a form of tetracycline has recently been used in
prevention of cancer recurrence.
• Tetracyclines may be used in the treatment of infections of the
respiratory tract, sinuses, middle ear, intestines.
• Gonorrhoea
72

• Acne
• Anthrax
• Bartonellosis
• Bronchitis- acute
• Brucellosis
• Gonorrhea
• Lower Respiratory Tract
Infections
• Helicobacter Pylori
• Sinusitis
• Amebiasis
• Gastric Ulcer
• Cholera
• Rocky Mountain Spotted
Fever
• Tularemia
• Syphilis
73

Contraindications of Tetracycline Antibiotics :
 Can stain developing teeth (even when taken by the mother during
pregnancy)
 Inactivated by Ca2+ ion, not to be taken with milk, yogurt, and other dairy
products.
 Skin photosensitivity; exposure to the Sun or intense light is not
recommended
 Drug-induced lupus, and hepatitis
 Can induce microvesicular fatty liver.
 May interfere with methotrexate by displacing it from the various protein
binding sites
74
:

• Tetracyclines should therefore
be avoided in pregnant or
lactating women.
• Tetracycline might cause
stains to developing adult
teeth,which cannot be easily
removed with conventional
tooth whitening.
• Tetracycline can
cause skin reaction.
75

• Mild nausea, vomiting, diarrhea.
• White patches or sores inside your
mouth or on your lips .
• Swollen tongue, trouble swallowing.
• Vaginal itching or discharge.
• Loss of appetite, jaundice (yellowing
of the skin or eyes).
76

77
 Do not use this medication if you are pregnant..
 Tetracycline passes into breast milk and may affect bone and tooth
development in a nursing baby.
 Do not give tetracycline to a child younger than 8 years old.
 Avoid exposure to sunlight or artificial UV rays.
 Do not take iron supplements, multivitamins, calcium supplements,
antacids.
 Throw away any unused tetracycline when it expires or when it is
no longer needed.

KEY POINTS
• The tetracyclines are bacteriostatic antibiotics that have a broad spectrum of activity and are the most
widely prescribed form of antibiotic after penicillins.
• The tetracyclines are broad-spectrum antibiotics that are active against both Gram-positive and Gram-
negative bacteria.
• The tetracyclines inhibit protein synthesis by binding to the 30S subunit of ribosomes and preventing
aminoacyl-tRNA from binding. This stops the further addition of amino acids to the growing protein chain.
Protein release is also inhibited.
• The tetracyclines were originally used for many types of respiratory infections, but have been largely
replaced by beta-lactams because of the problems of resistance. However, they are still the agents of choice
for the treatment of Lyme disease, rickettsia, and infections caused by chlamydia.
• They are also used to treat acne and a variety of different infections including respiratory and genital
infections. Doxycycline has been found to be useful for the treatment and prophylaxis of malaria, and is
cheaper than other antimalarial agents.
• The drug can also be used for the treatment of a variety of diseases including syphilis, sinusitis, oral herpes
simplex, and acne. It is a possible agent for the treatment or prophylaxis of anthrax.
• Tetracyclines should be avoided for young children and pregnant mothers since they can bind to developing
teeth and bone, leading to tooth discolouration.
• Resistance to tetracyclines can arise through several mechanisms. Some organisms have effective efflux
mechanisms that pump the drug back out of the cell. Resistance can also arise from alterations in the
bacterial ribosomes, such that they have lower affinity for the agents.
•
78

Tetracyclines are broad-
spectrum antibiotics. Despite
numerous reports of
resistance they are still the
drugs of choice for treatment
of a wide variety of infections.
79

Aminoglycoside antibiotics
• Amino glycoside antibiotics contain an amino cyclitol moiety to which
aminosugars are linked glycosidically.
• They may be more correctly called aminocyclitol antibiotics.Aminoglycosides are a
group of antibiotics effictive against gram+ve andgram-ve organismsas well as
micoplasma.
• Most of the aminoglycosides antibiotics are dirived from genus streptomyces
species, important one is streptomycin.
• 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.(pharmacophoric 1,3-diaminoinositol moiety consisting of
either streptamine,2-deoxystreptamine(Or) spectinamine.)
• Streptidine = streptomycin,Neomycin,Gentamycin, kanamycin,Tobramycin.
• All aminoglycosides in this class possess one amino hexose sugar.but some
antibiotics like Streptomycin, neomycin, paramomycin possess a pentonse sugar.
80

General characteristics of amino glycosides
• Amino glycosides are poly cations and are highly polar they are water
soluble.
• They are basic and form salts with acids.
• They are poorly absorbed after oral administration that’s why they do well
when given parentally.
• Because amino glycosides are quickly broken down in the stomach, these
antibiotics cant be given orally, but instead must be injected.
• Amino glycosides can cross the placental barrier.
• They are unable to cross blood brain barrier so they can’t be used for the
treatment of meningitis unless they are injected directly in to the CNS.
82

• Streptomycin is the first aminoglycoside antibiotic which was isolated from
the actinomycetes bacteria and several related soil microorganisms.
• It was isolated in 1943 from Streptomyces griseus, Major break through in
the treatment of tuberculosis in 1950.
• Chemistry of streptomycin. Streptomycin is a triacidic base and has an
aldose sugar.
• It is a water soluble with basic properties.
• The amino sugars attached to streptidine by means of glycosidic linkages.
• The methyl amino group attach to N-methyl-L-glucosamine exhibits
weakly basic natue.
• Streptomycin is made up of 3 basic structural units called ….
• Streptidine(a diguanidino compound)
• Streptose (a aldose sugar)
• N-methyl-L-glucosamine unit.
83

Physico- chemical properties
• Colour: colourless.
• Odour : odourless.
• State : Streptomycin sulphate ands treptomycin chloride available in the
form of whitepowdery solid.
• Solubility : Easily soluble in water insoluble in acetone.
• Stability: It is stable at a temp. less than 280c and solutions of streptomycin
are stable at pH (4.5-7).
85

SAR OF STREPTOMYCINE
• Modification of α-streptose portion of streptomycin has been extensively
studied.
1. Reduction of aldehyde to alcohol results in a compound dihyro streptomycin
activity is similar to streptomycin but producing severe deafness.
2. Oxidation of aldehyde group to a (oxime,semicarbazone,phenylhydrazone)
Schiff base derivatives results in inactive analogues.
3. Oxidation of –CH3 group in α-streptose to a methylene hydroxy gives an active
analogous but has no advantage over STM.
4. Modification of amino methyl group in the glucosamine by demethylation and
replace by larger alkyl groups reduces activity.
5. In N-methyl-L-glucosamine( –NHCH3 group) is very essential for the acivity.
6. Guanidino groups streptidine ring are essential. Replacement of guanidino
groups reduces the antibacterial activity.
7. In N-methyl –L-glucosamine the “N” atom should be secondary amine.
86

• Inhibition of protein biosynthesis initiation upon attachment to 30s portion
of ribosome's.
• Misreading mutation of the genetic code and the synthesis of nonsense
proteins which are not normal proteins so they cannot take part in cellular
activities.
• Nonsense proteins disturb the semi permeability of the bacterial cell and
Aminogylcoside molecules enter the cell easily and kill it.
• Also, there is evidence of inhibition of ribosomal translocation where the
peptidyl-tRNA moves from the A-site to the P-site
• They can also disrupt the integrity of bacterial cell membrane.
• Depending on their concentration they act as bactereostatic or bactericidal
agents.
• The protein synthesis inhibition of aminoglycosides does not usually
produce bactericidal effect.
• Recent experimental studies show that the initial site of action is the outer
bacterial membrane.
88

THERAPEUTIC USES OF AMINOGLYCOSIDES
• The most frequent use of aminoglycosides is empiric therapy for serious
infections such as septicaemia.
• complicated intra abdominal infections.
• complicated urinary tract infections,respiratory tract infections
Aminoglycosides are useful primarily in infections involving bacteria,such
aerobic gram –ve Pseudomonas, Actinobacter, and Enterobacter.
• In addition, some Mycobacteria, including the bacteria that cause
tuberculosis, are susceptible to aminoglycosides.
• In the past the aminoglycosides have been used in conjunction with beta-
lactamantibiotics in streptococcal infections for their synergistic effects,
particularly in enocarditis.
• One of the most frequent combinations is ampicillin (a beta-lactam, or
penicillin-related antibiotic) and gentamicin.
• .
•
89

Aminoglycosides toxicity
• Nephrotoxicity
• Ototoxicity
• Neuromuscular paralysis
90

IMPORTANCE OF DIHYDROSTREPTOMYCIN
• Treatment of tuberculosis in various animals. It is less
neurotoxic than streptomycin but high frequency of ototoxicity
in humans.
• Dihydro streptomycin is used in combination with procaine
penicillin to treat systemic infections.
• It is not recommended for humans as it is ototoxicity and
hence mostly used for veterinary purposes for the treatment of
systemic infections.
• The therapeutic dose in animals is 11mg/kg body weight given
through IM route.
92

CHLORAMPHENICOL (chloromycetin)
Chloramphenicol was originally derived from the bacterium Streptomyces venezuelae, isolated
by David Gottlieb, and introduced into clinical practice in 1949, under the trade name
Chloromycetin.
It was the first antibiotic to be manufactured synthetically on a large scale.
Chloramphenicol is a broad-spectrum antibiotic that acts as a bacteriostatic, but at higher
concentrations can act as a bactericidal.
A broad spectrum antibiotic which is a nitrobenzene derivative derived from dichloro
aceticacid.
Structure and chemical characteristics
Chloramphenicol contains a nitrobenzene ring, an amide bond, and an alcohol function.
The presence of chlorides in biologically produced organic molecules is unusual. The
nitrobenzene is relevant because it leads to the formation of aromatic amines which may be
carcinogenic.
The amide is hydrolyzed by some resistant bacteria leading inactivation.
The alcohol serves as a functional group facilitating the formation of esters that improve
chloramphenicols water solubility.
Chloramphenicol base has low water solubility and high lipid (in organic alcohols)solubility.
Its palmitate ester is similar, but the succinate ester has highwater solubility.
102

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