ANTIMIKROBIAL

DR.HUSNI SAMADIN
ANTIMICROBIAL CHEMOTHERAPY
CHEMOTHERAPEUTIC AGENTS
•Cmpounds used in treatment of diseases

ANTIMICROBIAL AGENTS
•Compounds used in treatment of microbial diseases

Categories of antimicrobial agents

•Antibiotics : biologically produced by microbes
•Synthetic
•Semi-synthetic : other chemical groups are added to
a nucleus of antibiotic
http://ssmmid.org
Antibiotic/Antimicrobial
•
Antibiotic: Chemical produced
by a microorganism that kills or
inhibits the growth of another
microorganism
•
Antimicrobial agent: Chemical
that kills or inhibits the growth of
microorganisms
Antimicrobial Agents
• Disinfectant: antimicrobial agent
used only on inanimate objects

• Chemotherapeutic agent:
antimicrobial agent that can be
used internally
Disinfection

• Pasteurization: destruction of all

disease-producing microorganisms
or reduction in spoilage
microorganisms

• Sterilization: killing or removal of all

living organisms and their viruses
 Characteristics of Antibacterial Agents
1.Selective Toxicity
• Inhibit growth of bacteria without damage to host
• Due to differences between bacterial and human cells
at four major sites:
° Cell wall
Few antiviral agents
° Cell membrane due to lack of
° Ribosomes selective toxicity

° Nucleic acids

http://ssmmid.org
Characteristics of Antibacterial Agents

2. Spectrum of Activity
Broad Spectrum:
•Active against both gram-positive and gram-negative
bacteria e.g. tetracycline, quinolones.
Narrow spectrum:
•Active against one or very few types of bacteria
Vancomycin for Staph. & Enterococci.

Metronidazole- antiamoebic and antiprotozoal.

http://ssmmid.org
Characteristics of Antibacterial Agents
3. Cidal vs Static
Bactericidal
Agents that kill bacteria
•Are useful in life-threatening infections
•Also useful in patients with low WBC count

Bacteristatic
Agents that inhibit but do not kill bacteria
•Bacteria may grow again when drug is withdrawn
•Host defences are needed to kill bacteria
•In large doses may become bactericidal
http://ssmmid.org
ANTIMICROBIALS : MECHANISMS OF ACTION
1.Inhibition of cell wall synthesis 2.Injury to plasma membrane
Penicillins, Cephalosporins Polymyxin B, Nystatin,
Vancomycin, Bacitracin Amphotericin B, Azoles

Transcription mRNA Transalation

Replication Proteins
Rifampicin 3. Inhibition of protein Synthesis
Quinolones Erythomycin, tetracyclin

5. Inhibition of nucleic
acid synthesis Enzymatic
activity

6. Uncertain site of action 4.Inhibition of enzymatic activity

Trimethoprim,
Metronidazole, INH
http://ssmmid.org
Sulphamethoxazole
Groups of Antimicrobial Agents
(Mechanisms of Action)

• Inhibitors of cell wall synthesis

• Inhibitors of cell membrane functions
• Inhibitors of protein synthesis
• Inhibitors of enzymatic activity
• Inhibitors of nucleic acids synthesis

http://ssmmid.org
 Site of action of inhibitors Cell wall synthesis
of cell wall synthesis
Cross-linking of
peptidoglycan
NAG
Beta-lactams
Fosfomycin
Transfer to
NAMA NAMA-pentapeptide peptidoglycan

+
Amino Lipid carrier Vancomycin
NAG
Acids (membrane)
Bacitracin

NAG = N-acetylglucosamine Dephosphorylation

NAMA = N-acetylmuramic acid of lipids

http://ssmmid.org
 Inhibitors of cell wall synthesis
A: BETA LACTAMS
Have a beta-lactam ring in their molecule
•Penicillins
•Cephalosporins
all are bactericidal
•Carbapenems
•Monobactams
B: GLYCOPEPTIDES
•Vancomycin & Teicoplanin

C: CYCLOSERINE & BACITRACIN

http://ssmmid.org
Inhibitors of cell wall synthesis
A: BETA LACTAMS
Penicillins
•Act by inhibiting cross-linking of peptidoglycan by
binding with penicillin binding proteins (PBPs) on
the cytoplasmic mamebrane – leads to :
°cell lysis
°ovoid cell
°filament cell
»Accoridng to type of PBPs
http://ssmmid.org
Action of penicillins on gram-
positive bacterial cell wall Penicillin

Capsule

Peptidoglycan
layer

Phospholipid
Tcytoplasmic PBP PBP
membrane

Transport protein

Cell lysis
Results of
action of Ovoid cell
penicillins
Filament

http://ssmmid.org
Inhibitors of cell wall synthesis
A: BETA LACTAMS
Penicillins e.g.
• Penicillin G
• Ampicillin, Amoxycillin
• Carbenicillin, Piperacillin – for pseudomonas
• Methicillin for penicillinase-producing
S. aureus

http://ssmmid.org
Inhibitors of cell wall synthesis
A: BETA LACTAMS
Cephalosporins
•Inhibit cross-linking of peptidoglycan
•Majority are produced by molds of genus cephalosporium
Advantage over Penicillins
•Broad range of activity
•Less susceptibility to b-lactamases
•Fewer hypersensitivity reactions

http://ssmmid.org
Inhibitors of cell wall synthesis
A: BETA LACTAMS
Cephalosporins
Generation Names Use Activity
First Cephradine I.M/I.V & G+ve bacteria
Cephalexin oral
Second Cefactor I.M/ I.V &G+ve + G-ve
oral
Third Cefotaxime I.M/I.V Mostly G-ve, G+ve
Ceftazidime Marked resistance
to beta-lactamases
Fourth Cefpirome I.M., I.V.
http://ssmmid.org
Inhibitors of cell wall synthesis
A: BETA LACTAMS

Carbapenems (imipenem, meropenem)

•Broadest activity of the b-lactams –G+ve, G-ve and
anaerobes
•Marked resistance to b-lactamases
Monobactams
•Selective activity against G-ve bacilli including
Pseudomonas
•Resistant to most b-lactamases

http://ssmmid.org
Inhibitors of cell wall synthesis
Vancomycin, Cycloserine, bacitracin
Block the formation of precursors of peptidoglycan
• Vancomycin - bactericidal against G+ve.
Drug of choice against MRSA
• Cycloserine - second-line anti-TB drug
• Bacitracin - for superficial skin infections

http://ssmmid.org
Inhibitors of Cell Membrane Functions

A. Antibacterials
•A few drugs in this group
•Due to structural similarity of bacterial and
human cell membranes
•Polymyxins – disrupt phospholips – leakage of
cell contents.

http://ssmmid.org
 Inhibitors of Cell Membrane Functions
B. Anti-fungals
1. Polyenes
•Act by binding with ergosterol in cell membrane – large
pores – leakage of cell contents
Nystatin, amphotericin-B, candicidin, trichomycin
2. Imidazoles
•Act by inhibiting ergosterol synthesis
Clotrimazole (Canesten) -Topical agents
Ketoconazole
Systemic agents
Fluconazole
 Inhibitors of protein synthesis : sites of action

Growing polypeptide
Chloramphenicol
50S
Tetracycline
tRNA
Erythromycin
Transcription
DNA mRNA
Direction of
30S
ribosome travel
Streptomycin

70S prokaryotic
ribosome
 Inhibitors of Protein Synthesis
Selective toxicity is due to differences in ribosomes
•In human cells 80S = 60S & 40 S subunits
•Bacterial cells 70S = 50S & 30S subunits
A. Drugs that act on 30S subunit
1.Aminoglycosides – Streptomycin
Gentamicin/Amikacin
•Change shape of 30S portion & blocks initiation of translation
•Are bactericidal
•Are toxic for kidneys and ears
•Poorly absorbed from GIT – given by injections
 Inhibitors of Protein Synthesis
A. Drugs that act on 30S subunit
2.Tetracyclines - Doxycycline
Minocycline

• Block attachment of tRNA to mRNA-ribosome complex

•Are bacteriostatic against G+ve & G-ve bacteria
mycoplasma, chlamydiae and rickettsiae
•Cause staining of teeth in young children
 Inhibitors of Protein Synthesis
Drugs that act on 50S subunit
1. Chloramphenicol
•Inhibit formation of peptide bond
•Bacteriostatic / Bactericidal
•Causes bone marrow suppression – aplastic anaemia
2. Macrolides
°Erythromycin,Clarythromycin, Azithromycin
•Prevent movement of ribosome along mRNA
•Bacteriostatic
•One of the least toxic drugs
Inhibitors of Nucleic acid synthesis

A. Inhibitors of mRNA synthesis

Rifampicin
• Inhibits mRNA synthesis by affecting
DNA-dependent polymerase of bacterial
cell without affecting human cells
• First-line anti-TB drug.
 Inhibitors of Nucleic acid synthesis
B. Inhibitors of DNA synthesis
1. Quinolones (naldixic acid)
•Inhibit DNA gyrase which maintains the supercoiling of
closed circular DNA
•Are broad spectrum bactericidal
2.Fluroquinolones
•Ciprofloxacin,Ofloxacin, Sparfloxacin
•Are broader spectrum than quinolones
•Damage growing bones so not given to pregnant women
and young children.
 Inhibitors of Nucleic acid synthesis
B. Inhibitors of DNA synthesis (anti-metabolites)
Para-aminobenzoic
3.Sulfonamides and acid (PABA)
trimethoprim Sulfamethxazole
Compete with PABA to
stop synthesis of folic Dihydrofolic acid
acid which is needed for
purine synthesis. These Trimethoprim
are used in combination

Tetrahydrofolic acid

Purines and other

DNA
precursors
Uncertain mechanisms of action

Isoniazid (INH), Ethambutol, Pyrazinamide

• Are first line anti-TB drugs
Metronidazole (Flagyl)
• Probably inhibit DNA synthesis
• Bactericidal against G-ve anaerobes and Protozoa
(Giardia and Trichomonas)
Chemoprophylaxis
• Is the use of antimicrobial agents to prevent
infections as:
A. In normal persons exposed to pathogens
• Rifampicin 600 mg twice daily during outbreaks
of meningitis.
• Isoniazid (INH) to prevent TB in those recently
infected.
• Tetracycline to prevent plaque
Chemoprophylaxis
B. In persons with high susceptibility to
infections
• Opportunistic infections– in immunosuppressed
persons like AIDS
• Recurrent urinary tract infections (UTI )
• Congenital and rheumatic heart diseases
C. Prior to Surgery
° Tooth extraction to prevent endocarditis
° Colorectal surgery to prevent peritonitis and
wound infections
Antimicrobial Resistance

• Relative or complete lack of effect

of antimicrobial against a previously
susceptible microbe

• Increase in MIC
 Asal usul Resistensi
A. Non genetic.
1. Mencegah akses
2. Menghilangkan agen antimkroba dari sel menggunakan
efflux pump
3. Inanktivasi agen anti mikroba melalui modifikasi dan
degradasi.
4. Modifikasi dari target antimikroba
B. Genetic.
1. Transfer gen.
2. Mutasi
 Mekanisme resistensi terhadap antimikroba

1. Mencegah akses
2. Menghilangkan agen antimkroba dari sel
menggunakan efflux pump
3. Inanktivasi agen anti mikroba melalui
modifikasi dan degradasi.
4. Modifikasi dari target antimikroba
 Mekanisme Resistensi Terhadap antimikroba
KHUSUS SARANA
MEKANISME
UNTUK MENCAPAI CONTOH
RESISTENSI
RESISTEN
Penghancuran cincin
beta-laktamase oleh
enzim. Dengan cincin Resistensi
beta-laktam hancur, staphylococi terhadap
antibiotik tidak akan penisilin;
lagi memiliki Resistensi
Enzimatik
kemampuan untuk Enterobacteriaceae
mengikat PBP terhadap penicllins,
(Penisilin-mengikat sefalosporin, dan
protein), dan aztreonam
mengganggu sintesis
dinding sel.
 Perubahan pengikat
protein penisilin
Perubahan Mutasi
untuk PBPs asli atau Resistensi
akuisisi PBPs akan terhadap
Perubahan
menyebabkan methicillin
sasaran
ketidakmampuan staphylococci
antibiotik untuk dan oksasilin
mengikat PBP dan
menghambat
sintesis dinding sel
 Menurun nya
pembentukan saluran
Porin Karena ini adalah di Enterobacter
mana beta-laktam aerogenes ,
menyeberangi membran Klebsiella
Penurunan
luar untuk mencapai PBP pneumoniae dan
serapan
dari bakteri Gram-negatif, Pseudomonas
perubahan dalam angka aeruginosa terhadap
atau karakter dari saluran imipenem
ini dapat mengurangi
penyerapan Betalactam ..
 Perubahan dalam struktur
molekul komponen dinding sel
Perubahan prekursor menurun mengikat Resistensi terhadap
sasaran vankomisin sehingga sintesis vankomisin enterococci
dinding sel mampu untuk
melanjutkan.

Enzim mengubah Memodifikasi

berbagai situs pada molekul
aminoglikosida sehingga Resistensi beberapa
Enzimatik kemampuan dari obat ini untuk bakteri negatif Gram-
modifikasi mengikat ribosom dan sintesis positif dan Gram untuk
protein berhenti sangat aminoglikosida
berkurang atau hilang sama
sekali.
 Perubahan angka atau
karakter saluran Porin
(melalui aminoglikosida yang Perlawanan dari
Penurunan melintasi membran luar berbagai bakteri Gram-
serapan untuk mencapai ribosom dari negatif untuk
bakteri gram negatif) aminoglikosida
sehingga penyerapan
aminoglikosida berkurang.

Modifikasi protein
ribosomal atau rRNA 16. Ini
Resistensi
mengurangi kemampuan
Perubahan sasaran Mycobacterium spp
aminoglikosida untuk
terhadap streptomisin
berhasil mengikat dan
menghambat sintesis protein
 Perubahan pada membran luar
mengurangi penyerapan obat Perlawanan Gram
dan / atau aktivasi pompa yang negatif dan
Penurunan menghilangkan kuinolon staphylococci
serapan sebelum konsentrasi (penghabisan
intraseluler cukup untuk mekanisme saja) untuk
metabolisme DNA berbagai kuinolon
menghambat.

Perubahan subunit girase DNA Gram negatif dan Gram

Perubahan menurunkan kemampuan positif ketahanan
sasaran kuinolon untuk mengikat enzim terhadap kuinolon
ini dan mengganggu proses DNA berbagai
Resistensi diperoleh melalui mutasi dan transfer gen horizontal

Mutasi adalah perubahan spontan dalam urutan DNA dalam gen

yang dapat menyebabkan perubahan dalam sifat yang kode untuk.
Setiap perubahan dalam pasangan basa tunggal dapat menyebabkan
perubahan yang sesuai pada satu atau lebih asam amino untuk yang
dikode, yang kemudian dapat mengubah enzim atau struktur sel
yang berakibat pada perubahan afinitas atau aktivitas antimikroba
yang efektif dari yang ditargetkan.

Dalam genom prokariotik, mutasi sering terjadi karena perubahan

dasar yang disebabkan oleh agen eksogen, kesalahan DNA
polimerase, penghapusan, insersi dan duplikasi
Transfer gen horizontal, atau proses swapping materi genetik
antara tetangga "kontemporer" bakteri, merupakan sarana
dimana resistensi dapat diperoleh. Banyak dari gen resistensi
antibiotik dilakukan pada plasmid, transposon atau integrons
yang dapat bertindak sebagai vektor yang mentransfer gen untuk
anggota lain dari spesies bakteri yang sama, serta bakteri di lain
genus atau spesies. Transfer gen horizontal dapat terjadi melalui
tiga mekanisme utama: transformasi, transduksi atau konjugasi.
Transformasi melibatkan pengambilan fragmen pendek DNA t
oleh bakteri alami . Transduksi melibatkan transfer DNA dari
satu bakteri ke lain melalui bakteriofag.. Konjugasi melibatkan
transfer DNA melalui pilus seksual dan membutuhkan sel-sel
kontak. Fragmen DNA yang mengandung gen resistensi dari
donor resisten, kemudian dapat membuat bakteri sebelumnya
rentan mengekspresikan perlawanan sebagai kode oleh gen
resistensi baru diperoleh.
What Factors Promote Antimicrobial Resistance?

• Exposure to sub-optimal levels of antimicrobial

• Exposure to microbes carrying resistance genes

Inappropriate Antimicrobiale use

• Prescription not taken correctly

• Antibiotics for viral infections
• Antibiotics sold without medical supervision
• Spread of resistant microbes in hospitals due to
lack of hygiene
Inappropriate Antimicrobial Use
• Lack of quality control in manufacture or outdate
antimicrobial
•
Inadequate surveillance or defective susceptibility assay
•
Poverty or war
•
Use of antibiotics in foods
Proposals to CombatAntimicrobial Resistance
• Speed development of new antibiotics
• Track resistance data nationwide
• Restrict antimicrobial use
• Direct observed dosing (TB)
Proposals to Combat
Antimicrobial Resistance

• Use more narrow spectrum

antibiotics
• Use antimicrobial cocktails
• Effect of combinations of drug.

Synergism occurs when the effect of

two drugs together is greater than the
effect of either alone.

Antagonism occurs when the effect of

two drugs together is less than the
effect of either alone.
Effects of Combinations of