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Patrick An Introduction to Medicinal Chemistry 3/e Chapter 19 ANTIBACTERIAL AGENTS

ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR (Structure Activity Relationship )

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Page 1: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Patrick

An Introduction to Medicinal Chemistry 3/e

Chapter 19

ANTIBACTERIAL AGENTS

Page 2: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Valinomycin and Gramicidin A

(Ionophores)

Act as ion carrier The peptides valinomycin and gramicidin A both act as ion-

conducting antibiotics (ionophores) and allow the uncontrolled

movement of ions across the cell membrane.

Page 3: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Valinomycin is a cyclic structure obtained from Streptomyces

fermentation

It contains three molecules of l-valine, three molecules of d-

valine, three molecules of l-lactic acid, and three molecules of

d-hydroxyisovalerate.

These four components are linked in an ordered fashion such

that there is an alternating sequence of ester and amide

linking bonds around the cyclic structure.

This is achieved by the presence of a lactic or

hydroxyisovaleric acid unit between each of the six valine

units.

Further ordering can be observed by noting that the l and d

portions of valine alternate around the cycle, as do the

lactate and hydroxyisovalerate units.

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Valinomycin acts as an ion carrier and could be

looked upon as an inverted detergent.

As it is cyclic, it forms a doughnut-type structure

where the polar carbonyl oxygens of the ester and

amide groups face inwards, while the

hydrophobic side chains of the valine and

hydroxyisovalerate units point outwards.

This is clearly favoured because the hydrophobic

side chains can interact via van der Waals

interactions with the fatty lipid interior of the cell

membrane, while the polar hydrophilic groups

are clustered together in the centre of the

doughnut to produce a hydrophilic environment

This hydrophilic centre is large enough to

accommodate an ion and it is found that a

‘naked’ potassium ion (i.e. one with no

surrounding water molecules) fits the space and

is complexed by the amide carboxyl groups

Page 5: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

• Valinomycin can, therefore, collect a potassium ion from the inner

surface of the membrane, carry it across the membrane and deposit it

outside the cell, thus disrupting the ionic equilibrium of the cell.

• Normally, cells contain a high concentration of potassium ions and a low

concentration of sodium ions.

• The fatty cell membrane prevents passage of ions between the cell and its

environment, and ions can only pass through the cell membrane aided by

specialized and controlled ion transport systems

• Valinomycin introduces an uncontrolled ion transport system which

proves fatal.

• Valinomycin is specific for potassium ions over sodium ions

• The real reason is that sodium ions do not lose their surrounding water

molecules very easily and would have to be transported as the hydrated

ion. As such, they are too big for the central cavity of valinomycin.

Page 6: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Ionophore Mechanism of action

Valinomycin disrupts the ionic equilibrium of a cell

Ionophores act on the plasma membrane and result in the uncontrolled

movement of ions across the cell membrane, leading to cell death.

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Gramicidin

• 15 Amino Acids: coil in helix: Hydrophobic-out and hydrophilic-in

• Gramicidin is a heterogeneous mixture of six antibiotic compounds, Gramicidins A, B and C, making up 80%, 6%, and 14% respectively

Page 8: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

More Ionophores:

used in veterinary

medicine

The ionophores nigericin ,

monensin A , and lasalocid

Function in much the same way as

valinomycin and are used in

veterinary medicine to control the

levels of bacteria

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Polymixin B

1. Can differentiate between different cellular plasma membranes Selectivity

• It causes the leakage of SMALL

MOLECULES (nucleoside) from the

cell rather than ions (valinomycin)

1. Injected intramuscular

2. Active against Pseudomonas strains that are resistant to antibacterial agents

3. Can be used topically

4. Has good activity against G –Ve

5. Less effective against G +Ve due to penetration problem (large MW)

Polypeptide

From soil bacteria

(Bacillus polymyxa) DAB: α,γ-diaminobutyric acid

primarily used for resistant

gram negative infections

Page 10: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Polymyxin B Mechanism of Action

1. Positively charged amino groups in the cyclic peptide

portion binds to a negatively charged site in the

lipopolysaccharide layer (an electrostatic attraction)

Alters cytoplasmic membrane permeability

1. Fatty acid portion dissolves in hydrophobic region of

membrane and disrupts membrane integrity

2. Leakage of cellular molecules, inhibition of cellular

respiration.

3. Binds and inactivates endotoxin

4. Relative absence of selective toxicity: nonspecific for cell

membranes of any type highly toxic

• Polymyxin B operates selectively on the plasma membrane of bacteria and

causes the uncontrolled movement of small molecules across the

membrane.

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Neosporin: Bacitracin, Neomycin, and

Polymyxin B

Antibiotic ointment used in the prevention of

infection and speeding the healing of wounds

Page 12: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Killer Nanotubes • Cyclic peptides with an even number of alternating D,L-

α-amino acid residues are known to self-assemble into

organic nanotubes

• Cyclic peptides with self-assemble properties

Killer Nanotubes

Self assembly of ‘killer nanotubes

Page 13: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

• Killer Nanotubes increase membrane permeability,

collapse transmembrane ion potentials, and cause rapid

cell death

• The nanotubes would allow molecules to leach out from

the cell and cause cell death.

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Killer Nanotubes

1. Stacking via hydrogen bonds (HB)

2. Hydrophobic R-groups in exterior

3. R-group modified for selectivity

(mammalian vs. bacterial)

4. Polar NH/CO in core

5. Work in progress

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Cyclic Lipopeptides New class of antibiotics

1. Daptomycin: derived from Streptomyces roseosporus

2. Disturbs cellular membrane functions

3. Used in treating skin infection

4. Active against MRSA

Decanoic chain

Page 16: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Daptomycin

Asp-X-Asp-Gly motif

The lipid portion of the molecule is derived from decanoic acid and the yield of product

obtained is increased if decanoic acid is added to the fermentation medium

• Cyclic peptides are being designed which will self-assemble to form

nanotubes in the cell membranes of bacteria

• Cyclic lipopeptides are a new class of antibiotic

Page 17: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

More Cyclic

Lipopeptides

Page 18: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Antibacterial Agents that Impair

Protein Synthesis (Translation)

Stages at which antibacterial agents inhibit translation

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Aminoglycosides: Streptomycin & Gentamycin C1a

Streptomycin (1944):

From Soil bacteria

(Streptomyces griseus)

first of a class of drugs

called aminoglycosides

and was the first

antibiotic remedy for

tuberculosis.

1. Basic Amine: At pH 7.4 the amine is +ve charge

2. The +ve charge help them to penetrate the outer cell wall of

Gram -ve.

They bind the 30S subunit and prevent the movement of

the Ribosome along the mRNA

2-deoxystreptamine (2-DOS)

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Page 21: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Inhibition of protein biosynthesis by

Aminoglycosides

Page 22: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

• Fast acting BUT might cause some ear and

kidney problems.

• Effective in treating infections caused by

aerobic Gram –Ve bacteria.

• The only compounds active against P.

aeruginosa

• Because of high polarity they have to be

injected.

• Not able to cross the BBB

Properties of Aminoglycosides

Page 23: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Streptomycin

Structure-activity Relationship

• Reduction of the aldehyde to the alcohol results in a compound,

dihydrostreptomycin, which has activity similar to STM but with

a greater potential for producing delayed severe deafness

(major side effect).

• Oxidation of the aldehyde to a carboxyl group or conversion to

Schiff’s base derivatives (oxime, semicarbazone, or

phenylhydrazone) results in inactive analogs.

• Oxidation of the methyl group in α-streptose to a methylene

hydroxy gives an active analog but with no advantage over

STM.

Page 24: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Streptomycin

Structure-activity Relationship

• Modification of the aminomethyl group in the glucosamine

portion of the molecule by demethylation or by replacement

with larger alkyl groups reduces activity.

• Removal or modification of either guanidine in the streptidine

nucleus results in decreased activity.

Page 25: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Streptomycin

• Metabolism

Page 26: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

More Aminoglycosides

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1949

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General structures of Kanamycins and ring I

substituents

Glucopyranosyl

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SAR of Gentamicin

Page 30: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Tetracyclines and Chloramphinicol

Tetracyclines:

Inhibit protein synthesis by

binding to 30S subunit and

preventing aminoacyl-tRNA

from binding

Chloramphenicol:

Binds to the 50S subunit and inhibit

the movement of the ribosome along

the mRNA, probably by inhibiting the

peptidyl transferase reaction by which

the peptide chain is extended.

Page 31: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Tetracyclines are bacteriostatic antibiotics which have a

broad spectrum of activity and are the most widely

prescribed form of antibiotic after penicillins. They are also

capable of attacking the malarial parasite

Tetracyclines cross the outer membrane of gram –ve bacteria

by passive diffusion through the porins

Commonly used tetracyclines in the clinic are tetracycline,

demeclocycline , doxycycline , lymecycline , minocycline , and

Oxytetracycline

The use of chlortetracycline has decreased over the years

because it kills the intestinal flora that produce vitamin K

Page 32: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

R5 R4 R3 R2 R1.

Chlortetracycline H H OH CH3 Cl

Oxytetracycline H OH OH CH3 H

Tetracycline H H OH CH3 H

Demethylchlortetracycline 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 32

Page 33: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

• 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:

• The amide hydrogen may be replaced with a methyl group, but

larger groups have a deleterious effect except for those which

are eliIminated spontaneously in water

• 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

33

Page 34: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

• 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

• 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

34

Page 35: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Side effect:

Dermatological:-Skin reactions, photosensitivity

GIT:-nausea, vomiting, and diarrhea.

CNS:-Dizziness,visual disturbances .

Immune System:-allergic reactions.

Other:-yellowish-grayish-brown discoloration of the

teeth.

35

Page 36: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

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

.

Oral contraceptives Concurrent use of tetracyclines with oral

contraceptives may render oral

contraceptives less effective.

36

Page 37: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Bile acid sequestrants

May decrease tetracycline

absorption

Iron preparations

May decrease absorption of

tetracyclines

Methoxyflurane when concurrent with tetracycline)

may cause fatal nephrotoxicity;

concurrent use is contraindicated.

Methotrexate: Clearance of methotrexate (high-

dose therapy) may be decreased by

tetracyclines.

Ergot alkaloids or their

derivatives are given with

tetracyclines.

Increased risk of ergotism

Drug interaction of tetracyclines

37

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Chloramphenicol is now prepared synthetically and has two

asymmetric centres. Only the R,R -isomer is active.

Chloramphenicol binds to the 50S subunit of ribosomes and appears

to act by inhibiting the movement of ribosomes along mRNA,

probably by inhibiting the peptidyl transferase reaction by which

the peptide chain is extended

The nitro group and both alcohol groups are involved in binding

interactions.

The dichloroacetamide group is also important, but can be replaced

by other electronegative groups. Chloramphenicol is quite toxic and

the nitro substituent is thought to be responsible for this

Page 39: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Macrolides

Erythromycins

• 14-membered macrocyclic lactone

• Sugars and amino-sugars attached

• Bind to 50S subunit of the bacterial ribosome

• Inhibiting translocation!!

Have similar antibacterial properties to macrolides

Lincosamides

Macrolides are bacteriostatic agents

Page 40: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Mechanisms of

Resistance

1. Methylation of the ribosomal

target of the antibiotics.

2. Antibiotic Efflux.

3. Drug Modification.

Page 41: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

One way to stabilize would be by:

1. Methylation (protection of OH groups e.g. clarithromycin)

2. Increasing the size to 16 –membered ring

Acid Instability of Erythromycin

Intra-molecular ketal formation in Erythromycin

Erythromycin is unstable to stomach acids, but can be taken orally

in a tablet form. The formulation of the tablet involves a coating

The acid sensitivity is due to the presence of a ketone and two alcohol groups

which are set up for the acid catalysed intramolecular formation of a ketal

Page 42: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Erythromycin

1. Erythromycin and Chloramphenicol bind to

the same region of the ribosome they

should not be administered together (in

effective).

2. Erythromycin is used against penicillin-

resistant staphylococci.

3. Best described against the legionaries’

disease, diphtheria, acne.

4. The acid instability of Erythromycin is solved

by coated tablet.

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Clarithromycin

1. More stable analogue of Erythromycin.

2. Improved oral absorption

3. Used in treatment of ulcers caused by H. Pylori

Resistance to Macrolides may be due to:

1) Efficient Efflux (pump the drug back out the cell)

2) Change in the binding site at the ribosome. Methylation

of the ribosomal target of the antibiotics (binding is

weakened)

3) Modification on the Macrolides by various enzymes

Page 44: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Increased stability acidic mediaNo intramolec. hemikatalisation

O

N

O

HOO

O

N

HO

HO

HO

O

O

O

OH

Azithromycin

Increased stability acidic mediaNo intramolec. hemikatalisationImproved ribosome binding, less resistansIncreased ribosome affinity

O

O

N

O

O

N

NN

O

MeOO

O

O

N

HO

Telithromycin

No intramolecular hemiketalizaion

Improved ribosome binding

Less Resistance

Increased ribosome affinity

contains a 15-membered macrocycle

where an N -methyl group has been

incorporated into the macrocycle. It is

one of the world’s best-selling drugs.

Page 45: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Telithromycin is a semi-synthetic derivative of erythromycin and

reached the European market in 2001.

The cladinose sugar in erythromycin has been replaced with a

keto-group and a carbamate ring has been fused to the

macrocyclic ring.

The two hydroxyl groups that cause the intramolecular ketal

formation in erythromycin have been masked, one as a methoxy

group and the other as part of the carbamate ring.

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Streptogramins

1. Bind to different regions of 50S

2. The binding of Dalfopristin

increases the affinity for

Quinopristin.

3. Quinopristin inhibits the

peptide chain elongation.

4. Dalfopristin interferes with the

transfer of the peptide chain

from tRNA to the other.

Parenteral

Gram-positive bacteria: Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Staphylococcus aureus, Some enterococci and especially

MRSA

Quinopristin

Dalfopristin

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Streptogramins

Pritinamycin is a mixture of macrolactone structures obtained from

Streptomyces pristinaespiralis .

Two of the components ( quinupristin and dalfopristin ) have been isolated.

These agents bind to different regions of the bacterial ribosome’s 50S

subunit form a complex.

It is found that binding of dalfopristin increases the binding affinity for

quinupristin, and so the two agents actin synergy with each other.

Quinupristin inhibits peptide chain elongation, while dalfopristin

interferes with the transfer of the peptide chain from one tRNA to the next.

Quinupristin and dalfopristin are protein synthesis inhibitors in a

synergistic manner. While each of the two is only a bacteriostatic agent, the

combination shows bactericidal activity.

Quinupristin Dalfopristin

Page 48: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Morpholine

NO

O

Oxazolidin-2-one

NH

HO

F

NO

Oxazolidinones

1. Broad Spectrum

2. Active against

strains that acquired

resistance to other

antibacterial agents.

3. They bind at much

earlier stage in the

protein synthesis.

S

The structure of Linezolide

Both oral and parenteral

Peptidyl transferase center (PTC)

They bind to 50S subunit and prevent the formation of

ribosome complex

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Oxazolidinones

• The oxazolidinones are a new class of synthetic antibacterial agents.

They inhibit protein synthesis at a much earlier stage than previous

agents, and, consequently, do not suffer the same resistance problems

• Before protein synthesis can start, a 70S ribosome has to be formed by

the combination of a 30S ribosome with a 50S ribosome. The

oxazolidinones bind to the 50S ribosome and prevent this from

happening. As a result, translation cannot even start.

• Other agents that inhibit protein synthesis do so during the translation

process itself

• Linezolid was the first of this class of compounds to reach the market in

2000, and by 2010, it was netting sales of £716 million per year

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• The oxazolidinones have a broad spectrum of activity and are active

against bacterial strains which have acquired resistance to other

antibacterial agents acting against protein synthesis

• Linezolid has good activity against most clinically important Gram-

positive bacteria, including MRSA. It can also be taken orally with

100% uptake from the gastrointestinal tract

• Unfortunately, there is a high level of side effects related to its use

and, as it is a bacteriostatic agent, there is a greater risk of bacterial

resistance developing

• Radezolid is one such structure which binds 10,000 times more strongly as a

result of extra binding interactions (extension the structure)

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Page 52: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Thiopeptide Antibiotics: Thiostrepton

• Thiopeptides are sulfur-rich macrocyclic peptides containing highly-modified amino

acids

• They have antibiotic activity against Gram-positive bacteria, but little or no activity

against Gram-negative bacteria

• They are characterized by a nitrogen-containing six-membered ring (such as

piperidine, dehydropiperidine, or pyridine) substituted with multiple thiazole rings

and dehydroamino acids

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Agents Acting on Nucleic

Acid Transcription Quinolones and Fluoroquinolones

1. They inhibit the replication and transcription of bacterial

DNA by stabilizing the complex formed between DNA and

topoisomerases

2. By forming a ternary complex (Drug-Enzyme-DNA)

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Nalidixic Acid

• First to be discovered-1962

• Active against G –ve

• Short-term UTI

• Bacteria can develop quickly resistance.

N N

O

OH

O

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Enoxacin

1. Wider spectrum of activity (G+ve and G-ve)

2. Active against highly resistant P. aeruginosa

3. 6-Flourine:

– Increased the activity

– Increased the cellular Uptake

N N

O

OH

O

N

F

HN

6

1 2

3

7 8

7-Piperazyl Improvements :

1. Oral absorption

2. Tissue distribution

3. Metabolic stability

4. Level of activity

5. Spectrum of activity (G-ve and P.

aeruginosa) 1980s

form a zwitterion with the

carboxylic acid group at position 3

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Ciprofloxacin

Cyclopropy substituent:

– Increase the spectrum

of activity (S. Aureus)

N

O

OH

O

N

F

HN

6

1 2

3

7 8

Replacement Nitrogen at position 8

with carbon Reduced side effects

1. Highly potent against G-ve

2. Used in treatment of wide range of infections: urinary,

respiratory, GI tract, skin, joints.

3. MOST ACTIVE BRAOD SPECTRUM ANTIBIOTIC

IN THE MARKET

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Bacterial Topoisomerase IV is

inhibited

Topoisomerase IV is predominantly responsible for separation of daughter DNA strands during cell

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1ST and 2nd generation

Fluoroquinolone limitations

1. The moderate activity against S. aureus.

2. The quick development of resistance

3. Only marginal activity against anaerobic

Streptococcus pneumoniae.

Third- and fourth-generation fluoroquinolones, such as ofloxacin,

levofloxacin , moxifloxacin, and besifloxacin began to be developed in

the early 1990s to tackle these issues

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• Ofloxacin has an asymmetric centre and is sold as a racemic mixture

of both enantiomers, one of which is active and one of which is not.

• Levofloxacin is the active enantiomer of oflaxacin and is twice as

active as the racemate.

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3rd Generation: Trovafloxacin and

others

3-azabicyclo[3.1.0]hexyl substituent at the C-7 position,

Developed by the 1990s

All of them are with improved activity against Streptococcus

pneumoniae

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Fluoroquinolone

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Rifamycin Antibiotics

• The rifamycins are natural products produced by Streptomyces mediterranei.

• This chemical class is an aliphatic chain forming a bridge

between two nonadjacent positions of an aromatic moiety.

• Semisynthetic derivatives are prepared via conversion of the

natural rifamycins to 3-formylrifamycin which is derivatized with

various hydrazines to give products such as rifampin and

rifapentine.

• Rifampin and rifapentine have significant benefit over previously

investigated rifamycins in that they are orally active, highly

effective against a variety of gram-positive and gram-negative

organisms, and have high clinical efficacy in the oral treatment

of tuberculosis.

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Rifamycin Antibiotics

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Rifamycin Antibiotics

Mechanism of Action:

• The rifamycins inhibit bacterial DNA-dependent RNA polymerase

(DDRP) by binding to the β-subunit of the enzyme leads to a

blocking of the initiation of chain formation in RNA synthesis.

• Rifamycins are highly active against rapidly dividing intracellular

and extracellular bacilli.

• Rifampin is active against DDRP from both gram-positive and

gram-negative bacteria but due to poor penetration of the cell

wall of gram-negative organisms by rifampin, the drug has less

value in infections caused by such organisms.

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Structure-activity Relationship:

o Free OH groups are required at C-l,8,21 and 23 as they are

important binding groups for attachment to DDRP.

o Acetylation of C-21 and C-23 produces inactive compounds.

o Reduction of the double bonds in the macro ring results in a

progressive decrease in activity.

Page 67: ANTIBACTERIAL AGENTS - acts on plasma membrane structure - SAR  (Structure Activity Relationship )

Structure-activity Relationship:

o Opening of the macro ring gives inactive compounds. These

latter two changes greatly affect the conformational structure of

the rifamycins which in turn decreases binding to DDRP.

o Substitution at C-3 or C-4 results in compounds with varying

degrees of antibacterial activity.

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Metabolism:

• Rifampin and rifapentine are readily absorbed from the intestine

although food in the tract may affect absorption.

• The major metabolism of rifampin and rifapentine is

deacetylation which occurs at the C-25 acetate to give

desacetylrifampin and desacetylrifapentine, which are still active

antibacterial agents.

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Therapeutic Application:

• Rifampin (Rifadin, Rimactane) is always used in combination with

one or more other antitubercular agents. The drug is potentially

hepatotoxic and may produce gastrointestinal disturbances, rash

and thrombocytopenic purpura (low levels of platelets that

prevents bleeding).

• Rifampin is known to induce CYP3A4 and CYP2C isoforms and may

decrease the effectiveness of oral contraceptives, corticosteroids,

Warfarin, quinidine, methadone, zidovudine, clarithromycin, and

the azole antifungal agents.

• Rifapentine is introduced for the treatment of pulmonary

tuberculosis and has major advantage over rifampin is the fact that

when used in combination therapy rifapentine can be orally

administered twice weekly during the "intense" phase of therapy

followed by once a week during the "continuous" phase of therapy.

• In contrast, rifampin is normally administered daily during the

"intense" phase of therapy followed by twice a week dosing during

the "continuous" phase of therapy.

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Summary

Aminoglycosides, tetracyclines, chloramphenicol, streptogramins,

lincosamides, and macrolides inhibit protein synthesis by binding to the

bacterial ribosomes involved in the translation process.

• Resistance can arise from a variety of mechanisms, such as drug efflux,

altered binding affinity of the ribosome, altered membrane permeability,

and metabolic reactions.

• Oxazolidinones prevent the formation of the 70S ribosome by binding to

the 50S subunit.

• Quinolones and fluoroquinolones inhibit topoisomerase enzymes, resulting

in inhibition of replication and transcription.

Rifamycins inhibit the enzyme RNA polymerase and prevent RNA

synthesis. In turn, this prevents protein synthesis. Rifampicin is used to treat

tuberculosis and staphylococcus infections. Fidaxomicin is a macrocycle

which also targets RNA polymerase.

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