Mechanism of action of

Antibiotics Antivirals
Antibiotics,
Antifungals and
Antimicrobial Resistance

Budiman Bela
T. Mirawati Sudiro

Dept. Mikrobiologi FKUI

References

KP Talaro. Foundation in Microbiology, 6th ed., 2008

PR Murray et.al.
et al Medical Microbiology,
Microbiology fourth edition
edition,
Mosby Inc.
GE Brooks,JS Butel,SA Morse. Jawetz, Melnick and
Adelbergs
Medical Microbiology, ed 24, , Appleton and Lange,
California. 2004
 Definition
Antibiotics: a chemical substance from one
microorganism
g that can inhibit or kill another
microbe even in minute amount

Antimicrobic: a special class of compounds capable

of destroying or inhibiting microorganism

Antimicrobial resistance:
the ability of microbes (bacteria,
(bacteria viruses
viruses, parasites
parasites,
or fungi) to grow in the presence of a chemical
(drug) that would normally kill it or limit its
growth.
 exposure selection expansion

sensitive population resistant clones outbreak, epidemic, pandemic

mrsa: a pandemic
http://www3.niaid.nih.gov/topics/antimicrobialResistance/Understanding/drugResistanceDefinition.htm
Accessed March 23, 2009
Antibacterial Agents
Red azo dye
y pprotosil:
1935
protection of mice against systemic streptococcal infection
curative in patients suffering from the same infection
Cleavage result in release of p-aminobenzene sulfonamide
(sulfonilamide) that possess antibacterial activity 1st sulfa
drug
Compounds produced by microorganisms that
inhibit the growth of other microorganism
(Antibiotic):
Al
Alexander
d fleming:
fl i the
th mold
ld Penicillium
P i illi prevented
t d the
th
multiplication of staphylococci
1940s: Streptomycin
1950s: Tetracyclines
Antibacterial Agent
New antibacterial agents have been
introduced and have to be continually
developed due to the remarkable ability of
bacteria to develop resistance to newly
introduced agents
Mode of action and target
molecules
l l off antibacterial
ib i l agents
Inhibition of cell wall synthesis
Inhibition of nucleic acid synthesis
I hibiti off protein
Inhibition t i synthesis
th i
Antimetabolites
Cell Wall Synthesis ! DNA Replication !
-Beta-lactams -Quinolones
-Vancomycin -Metronidazole
-Isoniazid
-Ethambutol
-Cycloserine RNA Synthesis
y
-Ethionamide -Rifampin
!
-Bacitracin -Rifabutin
-Polymyxin
DNA

Ribosomes
50 50 50
30 30 30
Protein synthesis !
Antimetabolites (50S ribosome)
-Sulfonamides
! -Chloramphenicol
-Dapsone -Macrolides
-Trimethoprim Protein synthesis -Clindamycin
-Para-aminosalicylic acid (30S ribosome)
! -Streptogramins
-Aminoglycosides
A i l id
-Tetracyclines
-Oxazolidinone
 Basic Mechanisms of Antibiotic Action
Antibiotic Action

Disruption of Cell Wall ! !

Penicillin Binds PBPs and enzymes responsible for peptidoglycan synthesis
Cephalosporin Binds PBPs and enzymes responsible for peptidoglycan synthesis
Cephamycin Binds PBPs and enzymes responsible for peptidoglycan synthesis
Carbapenem Binds PBPs and enzymes responsible for peptidoglycan synthesis
Monobactam Binds PBPs and enzymes responsible for peptidoglycan synthesis
-lactamase inhibitor/
-lactam Binds -lactamases and p prevents enzymatic
y inactivation of
-lactam
Vancomycin Inhibits cross-linkage of peptidoglycan layers
Isoniazid Inhibits mycolic acid synthesis
Ethionamide Inhibits mycolic acid synthesis
Ethambutol Inhibits arabinogalactan synthesis
Cycloserine
C l i I hibit cross-linkage
Inhibits li k off peptidoglycan
tid l llayers
Polymyxin Inhibits bacterial membranes
Bacitracin Inhibits bacterial cytoplasmic membrane and movement of peptidoglycan precursors

Inhibition of Protein Synthesis

Aminoglycoside
! Produces premature release of aberrant peptide chains from 30S ribosome
!
Tetracycline Prevents polypeptide elongation at 30S ribosome
Oxazolidinone Prevents initiation of protein synthesis at 30S ribosome
Macrolide Prevents polypeptide elongation at 50S ribosome
Clindamycin Prevents polypeptide elongation at 50S ribosome
Streptogramins Prevents polypeptide elongation at 50S ribosome
 Basic Mechanisms of Antibiotic Action

Antibiotic Action

!
Inhibition of Nucleic Acid Synthesis !
QQuinolone Binds subunit of DNA gy
gyrase
Rifampin Prevents transcription by binding DNA-dependent RNA polymerase
Rifabutin Prevents transcription by binding DNA-dependent RNA polymerase
Metronidazole Disrupts bacteria DNA (is cytotoxic compound)

Antimetabolite
Sulfonamides
Dapsone
p
! Inhibit dihydropteroate synthase and disrupt folic acid synthesis
Inhibits dihydropteroate
y p synthase
y
Trimethoprim Inhibits dihydrofolate reductase and disrupts folic acid synthesis !
 Mechanisms of resistance
Intrinsic resistance (chromosomal)
Acquired resistance
Gain
G i off function
f ti properties
ti
new enzymatic activity
phosphorylation,
phosphorylation acetylation
acetylation, pump
pump, etc.
etc
Mutation to existing proteins
alteration of ribosome subunits, cell wall
permeability, etc.
Inhibition of Cell Wall Synthesis
Interference with bacterial cell wall
synthesis
The most common mechanism of antibiotic
-lactam antibiotics:
Constitute
C tit t the
th majority
j it off cellll wall-active
ll ti
antibiotics
Penicilins,
P i ili Ch
Chepalosporins,
l i C
Cephamycins,
h i
Carbapenems, Monobactams, -lactamase
inhibitors
 Inhibition of Cell Wall Synthesis

Other antibiotics that interfere with

bacterial cell wall synthesis
Vancomycin:
Bacitracin
Antimycobacterial agents:
Isoniazid
Ethambutol
Cycloserine
Ethionamide
Inhibition of Cell Wall Synthesis by
B
Beta L
Lactam A Antibiotics
ibi i
Peptidoglycan layer:
Major structural component of bacterial cell
walls
! Basic structure:
A chain of 10 to 65 disaccharide residues
consisting of alternating molecules of:
N-acetylglucosamine and
N-acetylmuramic acid

! Chains of disaccharide residues are cross-

linked with peptide bridges rigid mesh
coating for bacteria
http://en.wikipedia.org/wiki/File:Gram-positive_cellwall-schematic.png
 Inhibition of Cell Wall Synthesis
y by
y Beta Lactam Antibiotics

Penicillin-binding
gpproteins ((PBPs):
)
Specific enzymes that build the peptidoglycan layer of
bacterial cell wall and can be bound by -lactam
antibiotics:
Transpeptidases
Carboxypeptidases
Endopeptidases
-lactam antibiotics generally act as bactericidal
agents:
Exposure of growing bacteria to -lactam antibiotics
binding with PBPs in the growing bacterial cell wall
inhibition of synthesis but not turnover (degradation) of
peptidoglycan bacterial cell death
Mechanisms of Bacterial Resistance
t
towards
d BBeta
t Lactam
L t Antibiotics
A tibi ti
1 Prevention of interaction between
1.
antibiotic and target PBP:
2 Decreased binding of antibiotic to PBP
2.
3. Hydrolysis of antibiotic by -lactamases
 Mechanisms of Bacterial Resistance towards Beta Lactam Antibiotics

1. Prevention of interaction between antibiotic and

target PBP:
Only seen in gram negative bacteria (particularly
Pseudomonas species):
Posession of outer membrane that overlies the
peptidoglycan layer
Penetration of -lactam antibiotics into gram-
negative bacilli requires transit through the outer
membrane pores:
Changes in the outer membrane pore proteins
(porins) alteration of the size or charge of the
porin channel exclusion of the antibiotic
 Mechanisms of Bacterial Resistance towards Beta Lactam Antibiotics

2 Decreased binding of antibiotic to PBP:

2.
! Formation of modified PBP that fails to bind
to
-lactam
lactam antibiotics but contributes to the
synthesis of the peptidoglycan layer
Origin of modified PBP:
Mutation in the PBP gene:
Streptococcus pneumoniae resistant to penicillins
Acquisition of a new PBP:
introduction of Escherichia coli PBP into
p y
Staphylococcus aureus confers resistance to oxacillin
 Mechanisms of Bacterial Resistance towards Beta Lactam Antibiotics

3. Hydrolysis of antibiotic by
-lactamases:
lactamases:
Inactivation of -lactam antibiotics
There are 200 different -lactamases:
lactamases:
Specific for penicilins: penicilinases
Specific for cephalosporins: cephalosporinases
Broad range of activity:
capable of inactivating most -lactam antibiotics
Extended-spectrum -lactamases ((ESBLs): )
Commonly encoded on plasmids can be
transferred from organism to organism : Causing
much difficulties and severely limit the empirical use
of -lactam
lactam antibiotics in some hospitals
 Mechanisms of Methicillin
R i
Resistance
The staphylococcal beta-lactamase protein, which
cleaves
l th
the bbeta-lactam
t l t ring
i structure,
t t confers
f
resistance to penicillin but not to semi-synthetic
penicillins such as:
methicillin,
thi illi oxacillin,
illi or cloxacillin.
l illi
Acquisition of the mecA gene, which codes for the
penicillin binding protein PBP2a ---- complete resistance
to all beta
beta-lactam
lactam antibiotics including the semisynthetic
penicillins.
PBP2a has a very low affinity for beta-lactam antibiotics,
and is thought to aid cell wall assembly when the normal
PBPs are inactivated.
The mecA gene is found on a large mobile genetic
element called the staphylococcal chromosomal
cassette mec (SCCmec).
Glycopeptides
A complex glycopeptide that disrupts cell wall
peptidoglycan
tid l synthesis
th i iin growing
i gram-positive
iti
bacteria
Interacts with D-alanine-D-alanine termini of the
pentapeptide
t tid side
id chains
h i interferes
i t f sterically
t i ll with
ith
the formation of the bridges between the peptidoglycan
chains
Used for the management of infections caused by
oxacillin-resistant staphylococci and other gram-
positive bacteria resistant to -lactam antibiotics
Inactive against gram
gram-negative
negative bacteria:
Molecule is too large to pass through the outer membrane and
reach the peptidoglycan target site
 Glycopeptides
y

Intrinsic resistance to Vancomycin:

Due to pentapeptide termination in D-
alanine-D-lactate
alanine D lactate does not bind
vancomycin:
Leuconostoc, Lactobacillus, Pediococcus and
Erysipelothrix
D-alanine-D-serine termination of
peptapeptide:
Enterococcus gallinarum, Enterococcus
casseliflavus
 Glycopeptides
y

Acquired resistance to Vancomycin:

Plasmid mediated
Enterococcus faecium and Enterococcus faecalis
A potential threat to the usefulness of vancomycin
for the treatment of enterococcal infections
Th
There is
i a concern that
th t if th
these genes are
transferred to staphylocci (proven by lab
experiments)
p ) highly
g y resistant and virulent
organism will emerge: Vancomycin resistant
Methicillin resistant Staphylococcus aureus
Polypeptides

Bacitracin:
Mixture of polypeptides
Inhibits cell wall synthesis
y by
y interfering
g with
dephosphorylation and the recycling of the lipid
carrier responsible for moving the peptidoglycan
precursors through the cytoplasmic membrane to
the cell wall
Also damage the bacterial cytoplasmic membrane
and inhibit RNA transcription
Resistance:
Failure of the antibiotic to penetrate into the bacterial cell
 Polypeptides
y
Polymixins:
Cyclic polypeptides
Inserted into bacterial membranes by interacting
with lipopolysaccharides and the phospholipids in
the outer membrane increased cell permeability
cell death
Most active against gram-negative bacilli since
gram-positive bacteria do not have
an outer membrane
Example:
Polymyxin B and E (colistin)
Isoniazid, Ethionamide, Ethambutol
anddC
Cycloserine
l i
Cell wall-active
wall active antibiotics for treatment
of mycobacterial infections
Isoniazid (INH):
Affect the synthesis of mycolic acid
Disruption
Di ti of:f
The desaturation of the long-chain fatty acids
The elongation of fatty acids and hydroxy lipids
 Isoniazid, Ethionamide, Ethambutol and Cycloserine
y

Ethionamide:
Derivative of Isoniazid
Blocks mycolic
y acid synthesis
y
Ethambutol:
Interferes with the synthesis of arabinogalactan in
the cell wall
Cycloserine:
Inhibition of D-alanine-Dalanine synthetase and
alanine racemase that catalyze cell wall synthesis
 Inhibition of Protein Synthesis
Aminoglycosides:
Example:
Streptomycin,
p y neomycin,
y kanamycin,
y tobramycin
y
Amikacin : synthetic derivatives of kanamycin
Netilmicin: synthetic derivatives of sisomycin
Able
Abl to
t pass through:
th h
Bacterial outer membrane (in gram-negative
bac e a)
bacteria)
Cell wall
Cytoplasmic membrane
 Inhibition of Protein Synthesis
y

Aminoglycosides:
Active site:
Cytoplasm
Binds to the 30S ribosomal proteins
Attachment to the ribosomes has two effects:
Production of aberrant proteins as the result of
misreading of the messenger RNA (mRNA)
Interruption of protein synthesis by causing the
premature release of the ribosome from mRNA
 Inhibition of Protein Synthesis
y

Aminoglycosides:
Bactericidal:
Able to bind irreversiblyy to ribosomes
Penetration through the cytoplasmic membrane:
Aerobic, energy dependent process
Anaerobic bacteria are resistant to aminoglycosides
Streptococci and Enterococci:
Cell wall of these bacteria can not be penetrated by
aminoglycosides
Treatment with aminoglycoside therefore requires an
inhibitor of cell wall synthesis (e.g. penicillin,
ampicillin, vancomycin)
 Inhibition of Protein Synthesis
y

Aminoglycosides:
Resistance (3 ways):
Mutation of the ribosomal binding site:
Relatively uncommon
Occurs in the genus Enterococcus
Decreased uptake of the antibiotic into the bacterial cell:
Observed in Pseudomonas
More commonly seen with anaerobic bacteria
Enzymatic
y modification of the antibiotic:
Modification occurs through: phosphorylation, adenylation and
acetylation of the amino and hydroxyl groups of the antibiotic
 Inhibition of Protein Synthesis

Tetracyclines
T t li
Broad spectrum, bacteriostatic antibiotics
Binding reversible to the 30S ribosomal subunits
Blocking the binding of aminoacyl-transfer RNA (tRNA) to the
30S ribosome-mRNA complex
Resistance:
Decreased
D d penetration
t ti off the
th antibiotic
tibi ti into
i t the
th bacterial
b t i l cell:
ll
Mutations in the chromosomal gene encoding the outer membrane
porin protein OmpfF low level resistance to the tetracyclines as
well as to other antibiotics (e.g. beta-lactams, quinolones,
chloramphenicol)
Active efflux of the antibiotic out of the cell:
A variety of genes in different bacteria control the active efflux of the
tetracyclines from the cell
The most common cause of resistance
Alteration of the ribosomal target site:
Production of proteins similar to elongation factors that protect the
30S ribosome antibiotic can still bind to the ribosome but protein
p
synthesis is not disrupted
Enzymatic modification of the antibiotic
 Inhibition of Protein Synthesis
y

Oxazolidones
Representative: Linezolid
Narrow-spectrum
p class of an antibiotics that block
initiation of protein synthesis by interfering with the
formation of the initiation complex at the 30S
ribosomal subunit crosscross-resistance
resistance with other
protein inhibitors does not occur can be used for
treatment of bacterial strains (Staphylococci,
streptococci
t t i and
d enterococci)
t i) th
thatt are resistant
i t t to
t
penicillins, vancomycin and the aminoglycosides
 Inhibition of Protein Synthesis
y

Chloramphenicol
p
Also disrupts protein synthesis in the human bone
marrow cells and can produce blood dyscrasias
Binding reversibly to the peptidyl transferase
component of the 50S ribosomal subunit blocking
peptide elongation
Resistance:
Plasmid-encoded chloramphenicol acetyltransferase
catalyze the acetylation of the 3-hydroxy group of
chloramphenicol
hl h i l incapable
i bl off bi
binding
di tto th
the 50S subunit
b it
Chromosomal mutations (less common) alter the outer
membrane porin proteins gram-negative bacilli become
less permeable
 Inhibition of Protein Synthesis
y

Macrolides
Bacteriostatic
Basic structure:
Macrocyclic lactone ring bound to two sugars
Reversible binding to the 50S ribosome blockage
of polypeptide elongation
Resistance:
Methylation
y of the 23S ribosomal RNA p prevents binding
g by
y
the antibiotic
Destruction of the lactone ring by erythromycin esterase
Active efflux of the antibiotic from the bacterial cell
 Inhibition of Protein Synthesis
y

Clindamycin:
Blocks protein elongation by binding to the
50S ribosome
Inhibits peptidyl transferase by interfering with
the binding of the amino acid-acyl-tRNA
acid acyl tRNA
complex
Resistance:
Methylation of the 23S ribosomal RNA
Inhibition of Nucleic Acid Synthesis
Quinolones
Synthetic chemotherapeutic agents
Inhibition of enzymes required for DNA
replication, recombination and repair:
DNA gyrases or topoisomerases:
Resistance (chromosomally mediated), 2
mechanisms:
Alteration of alfa subunit of DNA gyrase
Decreased drug uptake:
Changes in porin proteins on the bacterial surface
Biofilm
Some bacteria Interact of with each other to form a stickyy
web of bacteria and polysaccharides called a biofilm, which
adheres to a surface within a host (example: dental plaque,
on catether, pacemakers, intravenous devices, etc)
Bacteria in infectious biofilm tend to be 100x more drug
resistant to free bacteria caused by:
-Microbes
Microbes are protected by the thick impenetrable nature of
extracellular matrix
- bacteria slow their growth and less active
- microbes communicate in mass regulation of certain
resistance mechanisme, e.g. drug pump.
INHIBITION OF VIRAL REPLICATION BY
ANTIVIRAL AGENTS

Budiman Bela, T. Mirawati Sudiro

INTRODUCTION

The progress in development of antiviral chemotherapy

is much slower than that of antibacterial drugs
Viruses are obligate intracelluler parasites Viruses
use the host cells biosynthetic machinery and enzymes
---- it is more difficult to inhibit viral replication
without any toxicity to the host cells
 INTRODUCTION

Early antiviral drugs: targeted cells with extensive

DNA and RNA synthesis
Newer antiviral drugs are targeted toward :
- viral-
viral-encoded enzymes
- Structures of the virus that are important for
replication
The activityy of antiviral drugs
g is g
generally
y limited to
specific families of viruses:

Example:
anti reverse transcriptase for therapy of HIV
infection
 INTRODUCTION

Resistance to antiviral drugs:

is becoming more problematic due to the

higher rate of long-
long-term treatment of some
patients
Example:
resistance toward antiretroviral drugs
g in
people with AIDS

injudicious use of oseltamivir (Tamiflu)

may induce resistance of H5N1 influenza
virus towards the drug
Sintesis protein virus sebagai target antiviral ?
!
!
!
 !
Sintesis protein virus sebagai target antiviral ?

Sasaran antivirus yang kurang baik SEBAB tidak memungkinkan

inhibisi selektif terhadap sintesis protein virus (replikasi virus
memanfaatkan ribosom dan mekanisme sintesis sel pejamu)
Mekanisme terjadinya resistensi
a.l.:

- Inaktivasi protein yang mengaktifkan antivirus dalam sel,

misal : kinase timidin
- Perubahan target obat
Misal : reverse transcriptase, protease, GP41
Analog nukleosida
Dapat melakukan inhibisi selektif karena
karena::
1. Berikatan lebih baik dengan polimerasa DNA virus dibanding
polimerasa DNA sel
2. Obat digunakan lebih ekstensif pada sel terinfeksi, karena sintesis
DNAnya lebih cepat dibanding yang tidak terinfeksi
 Analog nukleosida

Acyclovir Valacyclovir
Acyclovir, Valacyclovir, Penciclovir dan Famciclovir:
- Memiliki rantai samping asiklik (bukan gula ribosa atau deoksiribosa)
- Bersifat selektif terhadap HSV (virus herpes simpleks) atau VZV (virus
zoster), karena kedua virus herpes tersebut menyandi kinase
varicella zoster)
timidin
- Kinase timidin virus mengaktivasi obat melalui fosforilasi (inisiasi
fosforilasi)
enzim
enzim--enzim sel pejamu melanjutkan proses pembentukan menjadi
bentuk difosfat kemudian ke bentuk trifosfat
- Pada sel tidak terinfeksi obat ini terdapat dalam bentuk tidak aktif karena
tidak terjadi inisiasi fosforilasi
- Bentuk trifosfat berkompetisi dengan guanosin trifosfat:
- menghambat
g p
polimerasa
- terminasi perpanjangan rantai DNA virus
- Digunakan 100x lebih banyak oleh DNA polimerasa virus dibanding oleh
DNA polimerasa sel
 Analog nukleosida

Ganciclovir:
- Aktif terhadap CMV
- CMV tidak menyandi kinase timidin, tetapi dapat melakukan
fosforilasi GCV oleh suatu kinase protein yang disandi
oleh virus ini
- Digunakan 30x lebih banyak oleh DNA polimerasa virus
dibanding
dib di oleh l h DNA polimerasa
li sell
- Digunakan dalam terapi antitumor dengan terapi gen
 NON NUCLEOSIDE
REVERSE TRANCRIPTASE INHIBITORS
Target obat anti HIV
 KEMOTERAPI ANTI VIRUS

NUCLEOSIDE ANALOG
Acyclovir (Acycloguanosine)
Lamivudine (3TC)
Ribavirin
Vidarabine (Adenine arabinoside)
Zidovudine
id di ((Azidothymidine
id h idi = AZT))

NUCLEOTIDE ANALOG
Cidofovir (HPMPC)

NON NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Nevirapine

PROTEASE INHIBITORS
Saquinavir
q
Indinavir
Ritonavir
 ANTI VIRUS TIPE LAIN
! AMANTADINE & RIMANTADINE
menghambat uncoating virus
virus Influenza A, profilaksis
FOSCARNET (Phosphonoformic acid = PFA)
menghambat DNA polimerase virus dan
reverse transcriptase
p
METHISAZONE
menghambat tahap akhir replikasi virus partikel
immature non infeksius poxvirus
virus immature,
OSELTAMIFIR (Tamiflu)
menghambat neuraminidasa virus influenza hambat
perakitan/budding
FUZEON
menghambat
g pperlekatan GP41 HIV ppada reseptor
p seluler
INTERFERON
 ANTIFUNGAL GROUP
POLYENES
AZOLES
ECHINOCANDINES
ANTI METABOLITES
FLUCYTOSINE
ALLYLAMINES
GRISEOFULVIN
TOPICAL
 SITES OF ACTION
OF ANTIFUNGAL AGENTS
 SYSTEMATICALLY ACTIVE ANTIFUNGAL
AGENTS
POLYENES
1. Amphotericin B (lipid formulation)
g
Treatment of serious life-threatening
mycoses
Poorly soluble in water and not
absorbed by the oral or intramuscular
route of administration
The lipid formulation is developed to
circumvent the nephrotoxic nature
 ANTIFUNGAL ACTION
1. Bind to ergosterol produce ion channels that
destroy the osmotic integrity of the fungal cell
membraneleakage of intracellular constituents and
cell death

2. Direct membrane damage caused by the generation

of a cascade of oxidative reactions triggered by the
oxidation of amphotericin B itself

R
Resistance
i t i associated
is i t d with
ith alterations
lt ti in
i
membrane sterols, usually a reduction in ergosterol
MECHANISM OF ACTION
 AZOLES

IMIDAZOLES
Two nitrogen molecules in the azole ring)
Only ketoconazole has systemic activitiy

TRIAZOLES
Three nitrogen molecules in the azole ring)
All have systemic activity
activity, include
fluconazole, itraconazole and voriconazole,
posiconazole, ravuconazole
 ACTIVITY
C

Inhibiting fungal cytochrome

cytochrome-450-dependent
450 dependent
enzyme lanosterol14-alpha-demethylase
(enzyme that involves in the conversion of
lanosterol to ergosterol) disrupts
membrane synthesis in the fungal cell
growth
th (fungistatic)
(f i t ti ) or cause cell
ll death
d th
(fungicidal)
 ECHINOCANDINS

Highly selective class of semisynthetic

lipopeptides that inhibit the synthesis of -
(1,3)-glucans, important contituents of the
fungal cell wall

Selective toxicity for fungi in which the

glucans play an important role in:
maintaining
i i i the
h osmotic i integrity
i i off the
h
fungal cell division and cell growth
 ANTIMETABOLITES
O S

FLUCYTOSINE (5
(5-fluorocytosine,
fluorocytosine, 5PC)

Fluorinated pyrimidine analogue interfere

DNA, RNA and protein synthesis

Enter the fungal cell via cytosine permease

and
a d deaminated
dea ated to 5
5-fluorouracil
uo ou ac (5-FU)
(5 U) in tthe
e
cytoplasm 5-FU converted into 5-
fluorouridylic acid compete with uracil in
the synthesis of RNA RNA miscoding and
inhibit DNA and protein synthesis
 ALLYLAMINES
Terbinafine (has systemic activity)
Naftifine (topical agent)
Inhibit
I hibit the
th enzyme squalene l epoxidase
id
decrease in ergosterol and increase in
squalene
l within
ithi ffungall cellll membrane
b
 GRISEOFULVIN
Oral
Oral, second-line agent in the treatment
of dermatomycoses

Inhibit fungal growth by interaction

with
ith microtubules
i t b l within
ithi the
th fungal
f l cell
ll
inhibit mitosis

Less effective than itraconazole and

terbinafine
G. Chamilos, D.P. Kontoyiannis, Drug Resistance Updates 8 (2005) 344358
344 358
G. Chamilos, D.P. Kontoyiannis, Drug Resistance Updates 8 (2005) 344358
G. Chamilos, D.P. Kontoyiannis, Drug Resistance Updates 8 (2005) 344358
 MECHANISMS OF RESISTANCE

POLYENES
Result of qualitative and quantitative alterations in the
fungal cell
Defective in ERG2 or ERG3 gene encoding for the C-8
sterol isomerase and C C-5
5 sterol desaturase

AZOLES
O S
Modification in the quantity/quality of target enzymes,
reduced access of the drug to the target, or combination
Point mutation in ERG11 encoding the target enzyme
(lanosterol 14-demethylase)altered
targetdecreased affinity for azoles