Antimicrobial Agents

Vilya Syafriana, M.Si.

PENDAHULUAN
Secara klinis, agen antimikroba
mengeluarkan toksisitas selektif terhadap
parasit dibandingkan ke inang.
Umumnya, sifat toksisitas tersebut terjadi
menyerang struktur atau proses mikroba
yang berbeda dari sel mamalia.
Sebagai contoh, beberapa agen menyerang
sintesis dinding sel bakteri, dan beberapa
lainnya pada fungsi ribosom bakteri 70S.
Beberapa antimikroba seperti penisilin,
bersifat nontoksik terhadap inang, kecuali
inang tersebut bersifat hipersensitif.

ISTILAH-ISTILAH
ANTIBIOTIK: antimikroba yang berasal
dari mikroorganisme. Antibiotik dihasilkan
oleh kelompok bakteri dan fungi.
ANTIMIKROBIAL: berbagai senyawa yang
memiliki aktivitas antimikroba yang cukup
sehingga dapat digunakan dalam
perawatan penyekit infeksi.
KEMOTERAPI: istilah yang biasa
digunakan dalam terapi kanker meliputi
antibiotik, antimikroba atau obat yang
digunakan.

 RESISTEN: organisme yang tidak

terhambat pertumbuhannyasecara klinis
meskipun konsentrasi agen mikroba
sudah sesuai takarannya.
SENSITIF: mikroorganisme yang
menunjukkan akan terhambat pada
konsentrasi antimikroba tertentu.
SUSCEPTIBLE: mikroorganisme yang
menunjukkan mereka akan terhambat
pada konsentrasi tertentu secara klinis.

 SPEKTRUM: kisaran dari

mikroorganisme terhadap antimikrobial
yang aktif.
Narrow spectrum: agen yang hanya
memiliki aktivitas terhadap beberapa
mikroorganisme
Broad spectrum: memiliki aktivitas
terhadap mikroorganisme yang lebih
beragam

SUMBER AGEN
ANTIMIKROBA
Antibiotik secara biologis berperan penting
dalam ekologi mikroba pada lingkungan
alaminya.
A.Antibiotik disintesis secara alami
oleh bakteri dan fungi
Sebagai contoh:
Penisilin: dari Penicillium
Cephalosporin: kapang
Streptomisin, tetrasiklin, kloramfenikol,
eritromisin: dari Streptomyces

2. Agen antimikroba disintesis secara

kimia
Agen-agen antimikroba yang disintesis
secara kimia ditemukan diantara senyawasenyawa yang disintesis untuk tujuan atau
pengujian efektivitas terapi terhadap
hewan.
Sebagai contoh, sulfonamida ditemukan
akibat penapisan rutin pewarna anilin.
Selain itu, bisa juga dengan merancang
struktur yang dapat berperan efektif dalam
menghambat atau sebagai kompetitor
dalam jalur metabolisme.

3. Agen antimikroba diperoleh

melalui manipulasi molekuler
Manipulasi secara molekuler bertujuan
menemukan antibiotik atau
kemoterapi untuk memperluas
jangkauan atau derajat aktivitas
menyerang mikroorganisme atau
untuk meningkatkan karakter
farmakologinya.
Sebagai contoh, pengembangan
penicillinase-resistant dan broadspectrum penicillin.

What properties should an

antibiotic have?
Selective toxicity is the most important
single attribute of an antibiotic
Antibiotics, like other chemotherapeutic
agents, need to be soluble in body
fluids, in order to exert their effect by
penetrating the body tissues.
The compound must not be
metabolised so quickly that it is excreted
from the body before having a chance to
act.

 if administered orally, it must not be

inactivated by the acid environment of the
stomach, and must be capable of being
absorbed by the small intestine.
an antibiotic should not have any significant
effect on the resident microflora of the
host.
it should not be easy for the target
pathogen to establish resistance against
an antibiotic.
side-effects such as allergic reactions should
be minimal.
it should be sufficiently stable to have a
good shelf life, without special storage
considerations.

How do antibiotics work?

1.
2.
3.
4.

Inhibition of cell wall synthesis (group I)

Disruption of cell membranes (group II)
Interference with protein synthesis (group III)
Interference with nucleic acid synthesis (group
IV)

SELECTED ANTIBACTERIAL
ANTIMICROBICS

1. Antimicrobics That Act on Cell

Wall Synthesis
The peptidoglycan (murein sac) component
of the bacterial cell wall gives it its shape
and rigidity
Mature peptidoglycan is held together by
cross-linking of short peptide side chains
hanging off the long glycan molecules.
This cross-linking process is the target
of two of the most important groups of
antimicrobics, the -lactams and the
glycopeptides (vancomycin and
teicoplanin)

-Lactam Antimicrobics
The -lactam antimicrobics comprise the
penicillins, cephalosporins,
carbapenems, and monobactams.
Their name derives from the presence of
a -lactam ring in their structure; this
ring is essential for antibacterial activity.
Penicillin, the first member of this class,
was derived from molds of the genus
Penicillium, and later natural -lactams
were derived from both molds and
bacteria of the genus Streptomyces.

 The -lactam antimicrobics interfere

with the transpeptidation reactions
that seal the peptide crosslinks
between glycan chains.
They do so by interference with the action
of the transpeptidase enzymes which carry
out this cross-linking.
The -lactams are classified by chemical
structure. They may have one -lactam
ring (monobactams), or a -lactam ring
fused to a five-member penem ring
(penicillins, carbapenems), or a sixmember cephem ring (cephalosporins).

 Glycopeptide Antimicrobics
Two agents, vancomycin and teicoplanin,
belong to this group.
Each of these antimicrobics inhibit
assembly of the linear peptidoglycan
molecule by binding directly to the
terminal amino acids of the peptide side
chains.
The effect is the same as with -lactams,
prevention of peptidoglycan cross-linking.
Both agents are bactericidal, but are primarily
active only against Gram-positive bacteria.

2. Inhibitors of Protein
Synthesis

Aminoglycosides
are active against a wide range of
bacteria, but only those organisms
that are able to transport them into
the cell by a mechanism that
involves oxidative phosphorylation.
Thus, they have little or no activity
against strict anaerobes or facultative
organisms that metabolize only
fermentatively (eg, streptococci).

 It appears highly probable that

aminoglycoside activity against facultative
organisms is similarly reduced in vivo when
the oxidationreduction potential is low.
Once inside bacterial cells,
aminoglycosides inhibit protein
synthesis by binding to the bacterial
ribosomes either directly or by involving
other proteins.
This binding destabilizes the ribosomes,
blocks initiation complexes, and thus
prevents elongation of polypeptide
chains.

 The agents may also cause distortion of

the site of attachment of mRNA,
mistranslation of codons, and failure to
produce the correct amino acid
sequence in proteins.
Eukaryotic ribosomes are resistant to
aminoglycosides, and the antimicrobics are
not actively transported into eukaryotic cells.
These properties account for their selective
toxicity and also explain their ineffectiveness
against intracellular bacteria such as
Rickettsia
and Chlamydia.

 Gentamicin and tobramycin are the major

aminoglycosides; they have an extended
spectrum, which includes staphylococci;
Enterobacteriaceae; and of particular
importance, P. aeruginosa.
Streptomycin and amikacin are now
primarily used in combination with other
antimicrobics in the therapy of tuberculosis and
other mycobacterial diseases.
Neomycin, the most toxic aminoglycoside,
is used in topical preparations and as an
oral preparation before certain types of
intestinal surgery, because it is poorly absorbed.

 Tetracyclines
Tetracyclines are composed of four fused
benzene rings. Substitutions on these rings
provide differences in pharmacologic features
of the major members of the group,
tetracycline, minocycline, & doxycycline.
The tetracyclines inhibit protein synthesis
by binding to the 30S ribosomal subunit
at a point that blocks attachment of
aminoacyl-tRNA to the acceptor site on
the mRNA ribosome complex.
their effect is reversible
they are bacteriostatic rather than bactericidal.

 Chloramphenicol
Chloramphenicol has a simple nitrobenzene
ring structure that can now be mass produced
by chemical synthesis.
It influences protein synthesis by binding
to the 50S ribosomal subunit and
blocking the action of peptidyl
transferase, which prevents formation of
the peptide bond essential for extension
of the peptide chain.
Its action is reversible in most susceptible
species; thus, it is bacteriostatic.
It has little effect on eukaryotic ribosomes,
which explains its selective toxicity.

 Macrolides
The macrolides, erythromycin,
azithromycin, and clarithromycin
They affect protein synthesis at the
ribosomal level by binding to the
50S subunit and blocking the
translocation reaction.
Their effect is primarily bacteriostatic.
Macrolides, which are concentrated in
phagocytes and other cells, are effective
against some intracellular pathogens.

 Clindamycin
Clindamycin is chemically unrelated to the
macrolides but has a similar mode of
action and spectrum with addition of
anaerobes.
It has greater activity than the macrolides
against Gram-negative anaerobes, including
the important Bacteroides fragilis group.
Streptogramins
They inhibit protein synthesis by binding
to different sites on the 50S bacterial
ribosome.
quinupristin inhibits peptide chain
elongation, and dalfopristin interferes
with peptidyl transferase

3. Inhibitors of Nucleic Acid

Synthesis

Quinolones
The target is DNA topoisomerase
(gyrase), the enzyme responsible for
nicking, supercoiling, and sealing
bacterial DNA during replication.
Bacterial topoisomerases have four
subunits, one or more of which are
inhibited by the particular quinolone.
Ex. ciprofloxacin, norfloxacin, and
ofloxacin,

 The fluoroquinolones are highly active

and bactericidal against a wide range of
aerobes and facultative anaerobes.
However, streptococci and Mycoplasma
are only marginally susceptible, and
anaerobes are generally resistant.
Ofloxacin has significant activity
against Chlamydia; whereas
ciprofloxacin is particularly useful
against P. aeruginosa.

 Folate Inhibitors
Bacteria must synthesize folate that
humans acquire in their diet
Folic acid is derived from paraaminobenzoic acid (PABA), glutamate,
and a pteridine unit.
The major inhibitors of the folate
pathway are the sulfonamides,
trimethoprim, para-aminosalicylic
acid, and the sulfones.

 Sulfonamides
Competition with PABA disrupts nucleic
acids.
The effect is bacteriostatic.
When introduced in the 1940s, sulfonamides
had a very broad spectrum (staphylococci,
streptococci, many Gram-negative bacteria)
but resistance developed quickly, and this
has restricted their use for systemic
infections.
Now their primary use is for uncomplicated
urinary tract infections caused by members
of the Enterobacteriaceae, particularly
Escherichia coli.

 Trimethoprim-Sulfamethoxazole
It competitively inhibits the activity
of bacterial dihydrofolate
reductase, which catalyzes the
conversion of folate to its reduced
active coenzyme form.
Activity against common bacteria and
some fungi

 Metronidazole
Action requires anaerobic conditions
The antibacterial action requires
reduction of the nitro group under
anaerobic conditions, which explains
the limitation of its activity to bacteria
that prefer anaerobic or at least
microaerophilic growth conditions.
The reduction products act on the cell at
multiple points; the most lethal of
these effects is induction of breaks
in DNA strands.

 Rifampin
Blocking of RNA synthesis occurs by
binding to polymerase
This agent is active against most Grampositive bacteria and selected Gramnegative organisms, including Neisseria
and Haemophilus but not members of the
Enterobacteriaceae.
The most clinically useful property of
rifampin is its antimycobacterial activity,
which includes Mycobacterium
tuberculosis and the other species that
most commonly infect humans.

4. Antimicrobics Acting on the

Outer and Cytoplasmic
Membranes

The polypeptide antimicrobics

polymyxin B and colistin have a
cationic detergent-like effect.
They bind to the cell membranes of
susceptible Gram-negative bacteria
and alter their permeability,
Their spectrum is essentially Gramnegative; they act against P. aeruginosa
and other Gram-negative rods.

How does antibiotic

resistance work?

Some bacteria are able to resist antibiotic

action by denying it entry to the cell;
Others can pump the antibiotic back out
of the cell before it has had a chance to
act, by means of enzymes called
translocases; this is fairly non-specific,
leading to multiple drug resistance.
Other bacteria are naturally resistant to a
particular antibiotic because they lack
the target for its action, for example,
Mycoplasma do not possess peptidoglycan,
the target for penicillins action.

 To avoid the action of an antibiotic,

bacteria may be able to use or develop
alternative biochemical pathways, so that
its effect is cancelled out.
Many pathogens can secrete enzymes that
modify or degrade antibiotics, causing them
to lose their activity;
we have already seen that penicillins can be
inactivated by enzymatic cleavage of their
-lactam ring. Similarly, chloramphenicol
can be acetylated, while members of the
aminoglycoside family can be acetylated,
adenylated or phosphorylated, all leading
to loss of antimicrobial activity.

 Mutations may occur which modify

bacterial proteins in such a way that they
are not affected by antimicrobial
agents.
You will recall that streptomycin normally
acts by binding to part of the 30S
subunit on the bacterial ribosome; the
actual binding site is a protein called
S12.
Mutant forms of the S12 gene can lead
to a product which still functions in
protein synthesis, but loses its ability to
bind to streptomycin.

 Similarly, mutations in
transpeptidase genes in
staphylococci means they do not
bind to penicillin any more, so
cross-linking of the cell wall is not
inhibited.

SELECTED ANTIVIRAL
AGENTS

1. Inhibitors of Attachment
Attachment to a cell receptor is a virus-specific event.
Antibody can bind to extracellular virus and prevent
this attachment.

2. Inhibitors of Cell Penetration

and Uncoating
Rimantadine and amantadine, these two
amines inhibit several early steps in viral
replication, including viral uncoating.
They are extremely selective, with activity
against only influenza A.

3. Neuraminidase Inhibitors
Oseltamivir and zanamivir are new
antivirals that selectively inhibit the
neuraminidase of influenza A and B viruses.
The neuraminidase cleaves terminal sialic
acid from glycoconjugates and plays a role in
the release of virus from infected cells.

4. Inhibitors of Nucleic Acid

Synthesis
At
present, most antiviral agents are
nucleoside analogs that are active against
virusspecific nucleic acid polymerases or
transcriptases and have much less activity
against analogous host enzymes.
Some of these agents serve as nucleic acid
chain terminators after incorporation into
nucleic acids.
Idoxuridine and Trifluorothymidine: block
DNA synthesis

 Acyclovir is unique in that it must be

phosphorylated by thymidine kinase to
be active, and this phosphorylation
occurs only in cells infected by certain
herpesviruses.
Acyclovir is effective against
herpesviruses that induce thymidine
kinase Inhibits viral DNA polymerase
and terminates viral DNA chain growth

 Valacyclovir, Famciclovir, and

Penciclovir
Agents that are similar to or become
acyclovir after absorption are available
Ganciclovir
Ganciclovir does not require viral
thymidine kinase for phosphorylation
inhibits the viral DNA polymerase.

5. Inhibitor of Viral RNA

Synthesis: Ribavirin
Unlike acyclovir, which replaces the ribose
moiety with an hydroxymethyl acyclic side
chain, ribavirin differs from guanosine in
that the base ring is incomplete and open.
Like other purine nucleoside analogs,
ribavirin must be phosphorylated to mono-,
di-, and triphosphate forms.
It is active against a broad range of viruses
in vitro, but its in vivo activity is limited.

Ribavirin has several modes of action

The triphosphate is an inhibitor of RNA
polymerase and it also depletes cellular
stores of guanine by inhibiting inosine
monophosphate dehydrogenase, an
enzyme important in the synthetic
pathway of guanosine.
Still another mode of action is by
decreasing synthesis of the mRNA 5 cap
because of interference with both
guanylation and methylation of the
nucleic acid base.

6. Inhibitors of HIV
Nucleoside Reverse Transcriptase Inhibitors
Azidothymidine (AZT), a nucleoside analog of
thymidine, inhibits the reverse transcriptase
of HIV.
Didanosine (ddI, dideoxyinosine) and zalcitabine
(ddC, dideoxycytidine) are nucleoside analogs
that inhibit HIV replication.
Stavudine (D4T) is another nucleoside analog
that inhibits HIV replication. D4T is a reverse
transcriptase inhibitor that also terminates
chain growth
Lamivudine (3TC), another reverse
transcriptase inhibitor

 Non-Nucleoside Reverse Transcriptase

Inhibitors (NNRTIs)
Compounds that are not nucleoside analogs
also inhibit HIV reverse transcriptase.
Several compounds, e.g., nevirapine, delavirdine,
and efavirenz, have been evaluated alone or in
combination with other nucleosides.
Protease Inhibitors
These agents block the action of the viralencoded enzyme protease, which cleaves
polyproteins to produce structural proteins.
Inhibition of this enzyme leads to blockage of
viral assembly and release.

7.Nucleotide Analogs
Cidofovir. inhibits viral DNA
polymerase

8. Other Antiviral Agents

Foscarnet, also known as
phosphonoformate, is a pyrophosphate
analog that inhibits viral DNA
polymerase by blocking the
pyrophosphate-binding site of the viral
DNA polymerase and preventing
cleavage of pyrophosphate from
deoxyadenosine triphosphate.
Interferons
Interferons are host cellencoded proteins
synthesized in response to double-stranded
RNA that circulate to protect uninfected cells
by inhibiting viral protein synthesis.