Antimicrobial Agents

Vilya Syafriana, M.Si.

PENDAHULUAN
Secara klinis, agen antimikroba
mengeluarkan toksisitas selektif terhadap
parasit ke inang.
Umumnya, sifat toksisitas tersebut
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 pertumbuhannya secara 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.
1.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 penyerangan terhadap
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

I. Antimicrobics That Act on Cell

Wall Synthesis
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.

-Lactam Antimicrobics
The -lactam antimicrobics comprise the
penicillins, cephalosporins,
carbapenems, and monobactams.
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.

 Glycopeptide Antimicrobics
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.
Two agents belong to this group: vancomycin
and teicoplanin. Both agents are bactericidal,
but are primarily active only against Grampositive bacteria.

II. Antimicrobics Acting on the

Outer and Cytoplasmic
Membranes

The polypeptide antimicrobics polymyxin B

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

III.Inhibitors of Protein
Synthesis

Terbagi menjadi beberapa kelompok:

A.Aminoglycosides
B. Tetracyclines
C. Chloramphenicol
D.Macrolides
E. Clindamycin
F. streptogramins

A. 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).

 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.

B. TETRACYCLINES
The tetracyclines inhibit protein
synthesis by binding to the 30S
ribosomal subunit at a point that
blocks attachment of aminoacyltRNA to the acceptor site on the
mRNA ribosome complex.
their effect is reversible
they are bacteriostatic rather than
bactericidal.

C. CHLORAMPHENICOL
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.

D.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.

E. 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.

F. STREPTOGRAMINS

They inhibit protein synthesis

by binding to different sites on
the 50S bacterial ribosome.
Quinupristin inhibits peptide
chain elongation
Dalfopristin interferes with
peptidyl transferase

IV.Inhibitors of Nucleic Acid

Synthesis

Terbagi menjadi beberapa kelompok:

A.Quinolones
B.Folate Inhibitor
C.Metronidazzole
D.Rifampin

A.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.

B. 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.

1. Sulfonamides
Competition with PABA disrupts
nucleic acids.
The effect is bacteriostatic.
Their primary use is for
uncomplicated urinary tract
infections caused by members of
the Enterobacteriaceae, particularly
Escherichia coli.

2. 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

C. METRONIDAZOLE
Action requires anaerobic or at least
microaerophilic growth conditions.
The antibacterial action requires
reduction of the nitro group under
anaerobic conditions.
The reduction products act on the cell
at multiple points; the most lethal of
these effects is induction of
breaks in DNA strands.

D. 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.

The most clinically useful property of

rifampin is its antimycobacterial activity,
which includes Mycobacterium tuberculosis.

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 nonspecific, 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 crosslinking 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

Most antiviral agents are nucleoside

analogs that are active against
virus specific 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.
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 viral-encoded 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 pyrophosphatebinding 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.