Antimicrobial

drugs

What are Antibiotics?

Where do they come from?
Antibiotics are molecules (low molecular weight
metabolites) produced by microorganisms that
kill other microorganisms or inhibit their
growth.
Streptomyces, Bacillus, Penicillium,
Cephalosporium

Many are now semi-synthetic or synthetic

Antimicrobial agent, Chemotherapeutic
agent

Ehrlich

1ST to use the term chemotherapy

Compound 606- arsenic to treat
syphilis

Domagk

Prontosil rubrum
Sulphanilamide
Isoniazid

Fleming,
Florey and Chain

Penicillin
(penicillin notatum)

Waksman (Schatz)

Isolated Streptomyces griseus

Streptomycin
Coined the term antibiotic
1ST randomized control
trial

SELECTIVE TOXICITY
The Central Concept of antimicrobial action.
The growth of the infecting organism is
selectively inhibited or the organism is killed
without damage to the cells of the host

Antibiotic Classification
Bactericidal vs. Bacteriostatic
Beta-lactams, vancomycin
Aminoglycosides,
Rif, Quinolones,
Anti-TB drugs
Anti-folates (2 used)
-cidal = kills, important for
serious infection or when
natural ability impaired
(diabetes, immune
disorders)

Tetracyclines, Macrolides,
Anti-folates (1 used)

-static = inhibits
bacterial growth,
allowing host defenses to
catch up

MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS

Mechanism of action include:
Inhibition of cell wall
synthesis
Inhibition of protein synthesis
Inhibition of nucleic acid
synthesis
Inhibition of metabolic
pathways
Interference with cell
membrane integrity

Inhibitors of Cell Wall Synthesis

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

Inhibition of Cell wall

synthesis:

Bacteria cell wall unique in construction

Antimicrobials that interfere with the

synthesis of cell wall do not interfere
with eukaryotic cell

Contains peptidoglycan

Due to the lack of cell wall in animal cells

and differences in cell wall in plant cell

Antimicrobials of this class include

lactam drugs
Vancomycin
Bacitracin

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Penicillins and
cephalosporins
Part of group of drugs called
lactams
Have shared chemical structure
called -lactam ring

Competitively inhibits function of

penicillin-binding proteins
Inhibits peptide bridge formation
between glycan molecules
This causes the cell wall to
develop weak points at the growth
sites and become fragile.

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

The weakness in the

cell wall causes the
cell to lyze.

MECHANISMS OF ACTION
OF ANTIBACTERIAL
DRUGS
The weakness in the cell wall
causes the cell to lyze.

Penicillins and cephalosporins are

considered bactericidal.

Penicillins are more effective

against Gram+ bacteria. This is
because Gram + bacteria have
penicillin binding proteins on
their walls.

MECHANISMS OF ACTION
OF ANTIBACTERIAL
DRUGS
The cephalosporins

Chemical structures make them resistant to

inactivation by certain -lactamases

Tend to have low affinity to penicillin-binding

proteins of Gram + bacteria, therefore, are most
effective against Gram bacteria.

Chemically modified to produce family of related

compounds

First, second, third and fourth generation cephalosporins

MECHANISMS OF ACTION
OF ANTIBACTERIAL
Vancomycin
DRUGS

Inhibits formation of glycan chains

Inhibits formation of peptidoglycans and cell wall

construction
Does not cross lipid membrane of Gram organisms.

Important in treating infections caused by penicillin

resistant Gram + organisms

Acquired resistance most often due to alterations in

side chain of NAM molecule

Prevents binding of vancomycin to NAM component of

glycan

MECHANISMS OF ACTION
OF ANTIBACTERIAL

Bacitracin
DRUGS

Interferes with transport of peptidoglycan

precursors across cytoplasmic membrane

Toxicity limits use to topical applications

Common ingredient in non-prescription firstaid ointments

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

Inhibition of protein synthesis:

Structure of prokaryotic ribosome acts as target for

many antimicrobials of this class

Differences in prokaryotic and eukaryotic ribosomes is

responsible for selective toxicity

Drugs of this class include

Aminoglycosides
Tetracyclins
Macrolids
Chloramphenicol

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

Aminoglycosides

Irreversibly binds to 30S

ribosomal subunit

Causes distortion and malfunction

of ribosome
Blocks initiation translation
Causes misreading of mRNA

Not effective against

anaerobes, enterococci and
streptococci

Often used in synergistic

combination with -lactam
drugs

MECHANISMS OF ACTION
OF ANTIBACTERIAL
Examples of
DRUGS
aminoglycosides
include

Gentamicin,
streptomycin and
tobramycin

Side effects with

extended use include

Ototoxicity
Nephrotoxicity

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

Tetracyclins

Reversibly bind 30S ribosomal

subunit

Blocks attachment of tRNA to

ribosome
Prevents continuation of protein
synthesis

Effective against certain Gram +

and Gram

Resistance due to decreased

accumulation by bacterial cells

Can cause discoloration of teeth

if taken by young child

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

Macrolids

Reversibly binds to 50S

ribosome

Prevents continuation of protein

synthesis

Effective against variety of Gram +

organisms and those responsible
for atypical pneumonia

Often drug of choice for patients

allergic to penicillin

Macrolids include

Erythromycin, clarithromycin and

azithromycin

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

Resistance can occur

via modification of RNA
target

Other mechanisms of
resistance include
production of enzyme
that chemically
modifies drug as well
as alterations that
result in decreased
uptake of drug

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

Chloramphenicol

Binds to 50S ribosomal subunit

Prevents peptide bonds from forming

and blocking proteins synthesis

Effective against a wide variety of

organisms

Generally used as drug of last resort

for life-threatening infections

Rare but lethal side effect is aplastic

anemia

MECHANISMS OF ACTION
OF ANTIBACTERIAL
DRUGS

Inhibition of nucleic acid synthesis:

These include
Fluoroquinolones
Rifamycins

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

Fluoroquinolones

Inhibit action of topoisomerase DNA gyrase

Topoisomerase maintains supercoiling of DNA

Effective against Gram + and Gram

Examples include

Ciprofloxacin and ofloxacin

Resistance due to alteration of

DNA gyrase

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

Rifamycins

Block prokaryotic RNA polymerase

Block initiation of transcription

Rifampin most widely used rifamycins

Effective against many Gram + and some Gram - as well

as members of genus Mycobacterium

Primarily used to treat tuberculosis and Hansens disease

as well as preventing meningitis after exposure to N.
meningitidis

Resistance due to mutation coding RNA polymerase

Resistance develops rapidly

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

Inhibition of metabolic
pathways:

Most useful are folate

inhibitors

Mode of actions to inhibit

the production of folic
acid

Antimicrobials in this class

include

Sulfonamides
Trimethoprim

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

Sulfonamides

Group of related compounds

Inhibit growth of Gram + and Gram - organisms

Substrate in folic acid pathway

Human cells lack specific enzyme in folic acid pathway

Through competitive inhibition of enzyme that aids in

production of folic acid

Structurally similar to para-aminobenzoic acid

Collectively called sulfa drugs

Basis for selective toxicity

Resistance due to plasmid

Plasmid codes for enzyme that has lower affinity to drug

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

Trimethoprim

Inhibits folic acid production

Interferes with activity of enzyme following enzyme

inhibited by sulfonamides

Often used synergistically with sulfonamide

Most common mechanism of resistance is plasmid

encoded alternative enzyme

Genes encoding resistant to sulfonamide and

trimethoprim are often carried on same plasmid

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS

Interference with cell

membrane integrity:

Few damage cell

membrane

Polymixn B most common

Common ingredient in firstaid skin ointments

Binds membrane of
Gram - cells

Alters permeability
Leads to leakage of cell and
cell death
Also bind eukaryotic cells but to
lesser extent
Limits use to topical
application

Antifungal
drugs

Classification
Fungal infections traditionally have been

systemic

divided into two distinct classes

superficial
The major antifungal agents are under
two major headings

systemic
topical

ANTIFUNGAL DRUGS
--by mode of action

Membrane disrupting
agents
Amphotericin B, nystatin
Ergosterol synthesis
inhibitors
Azoles, allylamines,
morpholine
Nucleic acid inhibitor
Flucytosine
Anti-mitotic (spindle
disruption)
Griseofulvin

Glucan synthesis
inhibitors
Echinocandins

Chitin synthesis
inhibitor
Nikkomycin

Protein synthesis
inhibitors
Sordarins, azasordarins

Systemic antifungal
agents
1.
2.
3.
4.

Amphotericin B
Flucytosine
Ketoconazole
Miconazole and Clotrimazole

Antifungal Drugs:
Outline

Polyenes (amphotericin B, nystatin)

Flucytosine
Azoles (imidazoles and triazoles)
Allylamines
Echinocandins
Griseofulvin
Other drugs

Drug targets

Antifungal Drugs

Polyenes:
Amphotericin B
Chemical properties - amphoteric
aqueous insolubility at neutral
pH

Amphotericin B.

Mechanism of Action
It binds to a sterol moiety, primarily ergosterol.
That is present in the membrane of sensitibe fungi.
By virtue of their interaction with the sterols of cell
membranes, polyenes appear to form pores or
channels.
The result is an increase in the permeability of the
membrane, allowing leakage of a variety of small
molecules, such as Na+. K+. H+

Amphotericin B.

Fungal resistance
Mutants selected in vitro for amphotericin B
reisistance replace ergosterol with certain
precursor sterols.

Nystatin

similar to amphotericin B

used topically and for GI use

used against candida and

dermatophytes (Epidermophyton,
Trichophyton, Microsporum).

Nystatin

Mechanism of action
A. Fungistatic and fungicidal
B. It binds to sterols, especially ergosterol, which
is enriched in the membrane of fungi and yeasts.
As a result of this binding, the drug appears to
form channels in the membrane that allow small
molecules to leak out of the cell.

H
N

Flucytosine
Mechanism of action

O
N

F
NH2

Flucytosine

It is converted within fungal cells, but not

in the hosts cell, to fluorouracil, a
metabolic antagonist that ultimately leads
to inhibition of thymidylate synthetase.

Mechanism of action

taken up into
permease

the

fungal

converted to 5-fluorouracil (5-FU) by cytosine

deaminase

5-FU eventually inhibits thymidylate synthetase

synthesized to 5-FUTP

incorporated into RNA.

cell

by

means

of

Uses

Systemic fungi, mainly candida, and

cryptococcus.

Fungistatic.

Used with amphotericin B (cryptococcal

meningitis) and with itraconazole
(chromoblastomyosis).

Azoles
Imidazoles
Triazoles

Mechanism
of action:

Ketoconazole

Blastomycosis, coccidioidomycosis,
ringworm, candidiasis; given orally.

Acid environment is needed to dissolve drug,

does not enter the CNS well.

Mechanism of Action
Inhibit the synthesis of ergosterol by blocking
demethylation (14-demethylase) of lanosterol also inhibit cytochrome activity.

Acetyl CoA
Squalene
monooxygenase

Squalene

Allylamine
drugs

Squalene-2,3 oxide
Lanosterol

Azoles

14--demethylase

(ergosterol)

Spectrum
imidazoles

of

Systemic fungi, dermatophytes

-fungistatic

Triazoles (a type of azole)

Itraconazole: uses
Histoplasmosis
Sporotrichosis
Aspergillosis
Blastomycosis

Topical Azoles

Clotrimazole
Miconazole
Econazole
Oxiconazole
Sertaconazole

Terconazole
Sulconazole
Tioconazole
Butoconazole

Allylamines
Inhibit squalene-2,3-epoxidase
(fungicidal)

Used to treat dermatophyte infections

Acetyl CoA
Squalene
monooxygenase

Squalene

Allylamine
drugs

Squalene-2,3 oxide
Lanosterol

Azoles

14--demethylase

(ergosterol)

Terbinafine

Inhibits squalene
2, 3- epoxidase.
Squalene is cidal to
sensitive organisms.

Used orally for

dermatophytes

Adverse effects
include hepatitis and
rashes. Both are rare.

Terbinafine

Naftifine, Amorolfine, and

Butenafine
Other

allylamines
For topical use

SORDARINS,
AZASORDARINS

EF3: A target in protein synthesis

machinery unique to FUNGI

Caspofungin

A large cyclic compound an echinocandin

Inhibits 1,3--D-glucan synthase, which is

required for glucan polymerization in the wall
of certain fungi

Used for aspergillosis and candidiasis

Adverse effects: fever, histamine release,

hypokalemia

This drug that may be synergistic with amphotericin B and

the azoles. It has activity against Candida species and Aspergillus species.

Griseofulvin
Mechanism of action

binds to microtubules comprising

the spindles and inhibits mitosis.

incorporates into keratin and

protects newly formed skin.

fungistatic
Spectrum

dermatophytes only

Other Drugs

Ciclopirox olamine - may block amino acid transport penetrates well - useful for candida and dermatophytes

Haloprogin - useful for dermatophytes and candida, may

cause burning

Tolnaftate - useful for dermatophytes - inhibits

synthesis of macromolecules

Undecylenic acid - dermatophytes

KI - taken orally for cutaneous sporotrichosis - may

cause a rash and irritation of salivary and lacrimal glands

Thank you ..