Antimicrobial drugs

Antibiotics

Lecture 1
By lecturer
Hayman Sardar Abd.
B. SC. Pharmacy
M. Sc. Medicinal Chemistry
Ph. D. Medicinal Chemistry
 Antimicrobial Drugs
• Chemicals used to treat microbial infection.

• Antimicrobial drugs include:

o Antibactrial drugs
o Antifungal drugs
o Antiprotozoal drugs
o Antihelminthic drugs
 Introduction
• The development of antibiotics over the past eight
decades has been one of medicinal chemistry’s
greatest success stories. However, on a cautionary
note, the pathogens are fighting back, and we humans
are locked in a never-ending arms race with these
microscopic adversaries. While deaths from bacterial
infections have declined markedly in the developed
world, deaths from bacterial infections are still
relatively common in the developing world.
• Worldwide, TB is one of the top 10 causes of death.
• Globally, 10.0 million people developed TB disease
in 2017.
• In 2017, TB caused an estimated 1.3 million deaths.
• In the developed world, multiple-resistant
Staphylococcus aureus (MRSA) is a growing
problem, with most new infections acquired in
hospitals. Deaths from MRSA infections are
becoming more common among elderly or
immunocompromised patients, and this has attracted
widespread publicity.
 Bacterial pathogens
• Bacteria are single-cell microorganisms that were first
observed by Anton van Leeuwenhoek in the 1670s, using
the microscope, which he had developed.
• In comparison with plant and animal cells, they are
relatively simple in structure.
• Bacterial cells lack clearly defined nuclei and organelles
which animal cells possess.
• The bacterial cell also has a quite distinct biochemistry;
possessing enzymes, which enable it to synthesize
essential vitamins which animal cells, can obtain directly
from food.
• Bacterial cells have cell membranes and cell walls,
whereas animal cells have only membranes.
• The cell wall is crucial to the bacterial cell’s survival,
enabling them to colonize a very wide range of
environments and osmotic pressures.
• The cell wall prevents the uncontrolled flow of water
into the cell and provides protection against a myriad
of hostile environmental factors such as heat, cold,
acidity, alkalinity, salinity and radiation.
• Bacteria can be characterized by a staining technique,
which allows them to be defined as Gram positive or
Gram negative.
• The staining technique involves the addition of a
purple dye followed by washing with acetone.
• Bacteria with a thick cell wall (20-40nm), made up of
peptidoglycan, absorb the dye and are stained purple
and are classed as Gram positive.
• Bacteria which possess a thin cell wall (<10nm)
absorb only a small amount of the dye, which is
washed out by acetone.
• They are stained pink by a second dye and are
defined as Gram negative.
• These latter also possess an outer membrane, made up
of liposaccharides, which is like the cell wall.
• Such differences in cell walls play a key role in the
targeting of both types of bacteria by antibacterial
agents.
 Mechanisms of Antibacterial action
• There are five principle mechanisms by which
antibiotics act:
1. Inhibition of cell wall synthesis: This results in the
construction of faulty cell walls, which are unable to
control the flow of water and nutrients in/out of cell,
lysis and cell death results.
2. Targeting of plasma membrane: The membrane
becomes permeable, resulting in cell death.
3. Antimetabolites Selectively target bacterial-enzyme
catalysis, impeding bacterial growth.
4. Inhibition of protein synthesis: Selectively block
synthesis of essential proteins and enzymes.
5. Inhibition of nucleic acid functions: Selectively
target transcription and replication, which impede
cell division.
• A substance is classified as an antibiotic if the
following conditions are met:
1. It has a product of metabolism (although it may be
duplicated or even have been anticipated by
chemical synthesis).
2. It is a synthetic product produced as a structural
analog of a naturally occurring antibiotic.
3. It antagonizes the growth or survival of one or more
species of microorganisms.
4. It is effective in low concentrations
The β-Lactam antibiotics
Penicillins
 O S CH3
H
R C N C CH C CH3
H 1 2
C N CH

O
COOH

1- β- lactam ring
2- Thiazolidine ring
 Penicillin G
• Active against Gram +ve bacilli and some Gram –ve
cocci.
• Nontoxic.
• Limited range of activity.
• Inactive orally, must be injected.
• Sensitive to β- lactamases.
• Same patients are allergic.
• Inactive against Stphylococci.
 SAR
• Amide & carboxylic acid are involved in binding.
• Carboxylic acid binds as the carboxylate ion.
• Mechanism of action involves the β- lactam ring.
• Activity related to β- lactam ring activity (stability)
(subject to stability factors).
O S CH3
H
R C N C CH C CH3
H 1 2
C N CH

O
COOH
• Bicyclic system increases β- lactam ring stability.
• No much variation in structure modification is
possible.
• Variations are limited to side chain (R).

O S CH3
H
R C N C CH C CH3
H 1 2
C N CH

O
COOH
 Mechanism of action
• Penicillin inhibits a bacterial enzyme called the
transpeptidase enzyme which is involved in the
synthesis of the bacterial cell wall.
• The β- lactam ring is involved in the mechanism of
inhibition.
• Penicillin becomes covalently linked to the enzyme’s
active site leading to irreversible inhibition.
 Problems with Penicillin G
• Sensitivity to stomach acids.
• Sensitivity to β- lactamases enzymes which hydrolyze
the β- lactam ring.
• Limited range of activity.
 Acid sensitivity
• Reasons for sensitivity
1. Ring stability

O O S
O S S CH3
CH3 CH3
H H
H R C N C CH C CH3
R C N C CH C CH3 R C N C CH C CH3
Acid or Enzyme H H
H
HO C N CH HO C HN CH
C N CH

H 2O O O O COOH
COOH H COOH
2. Reactive β- lactam carbonyl group does not behave
like a tertiary amide

O S O
CH3 S CH3
H H
R C N C CH C CH 3 R C N C CH C CH3
H H
C N CH X C N CH

O O
COOH COOH

Impossible strain

Interaction of nitrogen’s lone pair with the carbonyl

group is not possible, results in reactive carbonyl
group
3. Acyl side chain
Neighboring group participation in the hydrolysis
mechanism

H R N R N
R C N C CH CH CH CH CH
H
O H
C N O C N O C HN
O
O H O

Further reactions
(unreactive products)
• In conclusion, the β- lactam ring is essential for
activity & must be retained, therefore can’t tackle
factors 1 & 2.
• Only factor 3 can be tackled.
• Vary the acyl side group (R) to make it electron
withdrawing to decrease the nucleophilicity of the
carbonyl oxygen.
H
G.W.E C N C CH
H

O C N

O
• Better acid stability & orally active, but sensitive to
β– lactamases is obtained with Penicillin V.
• Slightly less active than penicillin G with allergy
problems with some patients.

H
PhO C C N C CH
H2 H

O C N

O
Penicillin V
(orally active)
• Very successful semi synthetic penicillins like
ampicillin & oxacillin

H
R C C N C CH
H H

O C N

X = NH2, Cl2, PhOCONH, COOH

and Hetrocycles
 Sensitivity to β- lactamases
• β- lactamase enzyme is the enzyme that inactivate
penicillins by opening β- lactam rings, that allow
bacteria to be resistant to penicillin.
• β- lactamase is transferable between bacterial strains
(bacteria can acquire resistance).
• 80% of staphylococcus aureus infections in hospitals
were resistant to penicillin and other antibacterial
agents by 1960.
 • Mechanism of action for lactamases is identical to the
mechanism of inhibition for the target enzyme, but
product is removed efficiently from the lactamase
active site.

O
O
H
H N
N S CH3
S CH3 CH
CH
ß- lactamase R
R
C HN CH3
N CH3
O
O OH
COOH
COOH
• Block access of enzyme active site to penicillin by
introducing bulky groups to the side chain of
penicillin to act as a steric shields.
• Size of the shield is crucial to inhibit reaction of
penicillin with β- lactamases but not with the target
enzyme (transpeptidase).
O
H
N
S CH3
CH
R

ß- lactamases N CH3

O
COOH
• Methicillin :
• Methoxy groups block access to β- lactamases but not
to transpeptidases.
• Active against some penicillin G resistant strains
(staphylococcus).
• Acid sensitive & must be injected.
• Lower activity compared to penicillin G (reduced
access to transpeptidase).
• less range of activity.
• Poor activity against some streptococci.
• Inactive against Gram –ve bacteria.
O
H
OMe N
S CH3
CH
OMe
N CH3

O
COOH
• Oxacillin
• Orally active & acid resistant.
• Resistant to β- lactamases.
• Active against staphylococcus aureus.
• Less active than other penicillin.
• Inactive against Gram –ve bacteria
• Nature of R & R’ influences absorption & plasma
protein binding.
• Cloxacillin better absorbed than Oxacillin.
• Flucloxacillin less bound to plasma protein, leading
to higher levels of free drug.
 R'
O
H
N
S CH3
CH

N CH3
R N
O Me O
COOH

Bulky & E.W.D Oxacillin R= R'= H

Cloxacillin R= Cl, R'= H
Flucloxacillin R= Cl, R'= F
 Range of activity
Factors affecting range of activity:
1. Cell wall may have a coat preventing access to the
cell.
2. Excess transpeptidase enzyme may be present.
3. Resistant transpeptidase enzyme (modified
structure).
4. Presence of β- lactamases.
5. Transfer of β- lactamases between strains.
6. Efflux mechanism
 Results of varying R in Penicillin G
1. When R is hydrophobic, this results in high activity
against Gram +ve bacteria & poor activity against
Gram –ve bacteria.
2. Increasing hydrophobicity has little effect on Gram
+ve activity but lowers Gram –ve activity.
3. Increasing hydrophilic character has little effect on
Gram +ve activity but increases Gram –ve activity.
4. Hydrophilic groups at α position (eg. NH2, OH,
COOH) increases activity against Gram –ve
bacteria.
 Aminopenicillins
• Have NH2 at the α position.
• Ampicillin & Amoxycillin

H NH2
H NH2
HO C
C H
H N
N S CH3
S CH3
O O
N CH3 N CH3
O O
COOH COOH
Ampicillin Amoxycillin
• Properties: active against Gram +ve & Gram –ve
bacteria which don’t produce β- lactamases.
• Acid resistant & orally active,
• Nontoxic.
• Sensitive to β- lactamases
• Increased polarity due to extra amino group.
• Poor absorption through the gut wall.
• Disruption of gut flora lead to diarrhoea.
• Inactive against Pseudomonas aeruginosa.
 O

Prodrugs of Ampicillin R= CH2O

Pivampicillin
C
OCH3

H NH2

• Properties: C
H
N S CH3
O
N CH3 R= O
O
COOR

O Talampicillin

H C
R= C O O CH2CH3
• Increased cell membrane permeability. CH
Bacampicillin
3

• Polar carboxylic acid group is masked by the ester

• Ester is metabolized in the body by esterases to give
the free drug
 β- lactamase inhibitors H
O OH

• Clavulanic acid
N
O
O

•
H
Weak, unimportant antibacterial activity.
O K
• Powerful irreversible inhibitor of β- lactamases.
• Used as a sentry drug for ampicillin
• Augmentin® = amoxicillin + clavulanic acid or
• Allows less amoxicillin per dose & an increased
activity spectrum.
• Other β- lactamase inhibitors include:

• Sulbactam
• Tazobactam
• Avibactam *
• Vaborbactam *
• Relebactam *
 Carboxypenicillins
• Containing COOH at α position
• Carbenicillin:
• Active over a wider range of Gram –ve bacteria than
ampicillin
• Active against Pseudomonas aeruginosa.
• Resistant to most β- lactamases. O Na O

• Less active against Gram +ve bacteria. H

N

• Acid sensitive & must be injected.

S CH3
CH

O N CH3

Carbenicillin O
Na O
• Prodrug of carbenicillin
• Acid resistance & taken orally

O O

H
N
S CH3
CH

O N CH3

Carbenicillin indanyl sodium O

Na O
• Ticarcillin:
• Administered by injection.
• Identical antibacterial spectrum to carbenicillin.
• Smaller doses required compared to carbenicillin.
• More effective against Pseudomonas aeruginosa
fewer side effects O OH

• Can be administerd with clavulanic acid. H

N
S CH3
CH

O N CH3
S
O

Ticarcillin O
HO
 Ureidopencillins
• Urea group at the α position.
• Administered by injection.
• Generally, more active than Carboxypenicillins
against Streptococci & Haemophilus species.
• Generally, have similar activity against Gram –ve
aerobic rods.
• Generally, more active against Gram –ve bacteria.
• Azlocillin is effective against Pseudomonas
aeruginosa.
• Piperacillin can be administered alongside
Tazobactam.
 O
O

R= HN N
RN NH
H
N Azlocillin
S CH3
CH

O N CH3

O R=
Et N N
O
HO

O O
Piperacillin

O
R=

MeO2S N N

Mezlocillin
Thank you