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Chemotherapeutic Agent

= are compounds that destroys pathogenic microorganism
or inhibit their growth.
= one of the most valuable method of treating infection
= most common agents used are: antibiotics, microbial
products or their derivatives that are capable of
killing susceptible microorganism or inhibiting their
growth

Antibiotics:
= are naturally occurring metabolic products of primarily
soil bacteria & fungi
= these substances functions to limit microbial growth in
soil environment by killing or inhibiting their growth
= some are semi-synthetic in which the natural active
component in the molecule is combined with a
synthetic group
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Desirable Properties of Chemotherapeutic Agent:

1. Selective toxicity
2. Bactericidal rather than bacteriostatic
3. Should not be allergenic
4. It should remain active in the presence of plasma,
body fluids and exudates
5. Should have broad-spectrum activity
6. Water soluble and stable
7. Susceptible organism should not become resistant
8. Cheap


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Antibiotic producing organism:
A) Bacteria
a.1. Bacillus
a.2. Streptomyces

B) Fungi
b.1. Penicillium
b.2. Cephalosporium
b.3. Micromonospora


Mech. of action:
1. Interfere with cell wall synthesis
2. Interfere with cell membrane function
3. Interfere with Protein synthesis
4. Interfere with nucleic acid metabolism


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I. Cell Wall Inhibitors:

1.1. B lactam antibiotics
A. Penicillin
= product of the green mold penicillium notatum
= basic structure consist of thiazolidine ring joined
to a B-lactam ring
= MOA: affect bacteria by interfering with the
normal maintenance and synthesis of
bacterial cell wall
= inhibit the transpeptidation enzyme involve in cell
wall synthesis
= have a B-lactam ring structure that is inactivated
by B-lactamase which are genetically coded in
some bacterial DNA and some R plasmid
= reacts with penicillin-binding protein
= active against both gram positive and gram
negative bacteria

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a.1. Natural occurring Penicillin

Benzylpenicillin / Penicillin G
= first antibiotic to be widely used in medicine
= administered parenterally
= inactivated by acidic pH of gastric juice
= destroyed by B-lactamase
= highly effective against gram positive and less
effective against gram negative bacteria


Phenoxymethylpenicillin / Penicillin V
= similar to penicillin G
= more stable in acid medium
= can be given orally


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a.2. Semisynthetic Penicillin
= are derivative of 6-aminopenicillamic acid
= most crucial feature is the B-lactam ring which
appears to be essential for biologic activity
1) Penicillinase-resistant penicillin
1.1. Includes: Methicillin and Nafcillin
= drug of choice for penicillinase-resistant organism
= penicillinase, the enzyme synthesized by many
penicillin-resistant bacteria which destroys
activity by hydrolyzing a bond in the ring
= less active than penicillin G
= acid-labile

1.2. Isoxazolyl PCN (Oxacillin, Cloxacillin & Dicloxacillin)
= resistant to B-lactamase and gastric acid
= drug of choice for PCN-resistant S. aureus and
S. epidermides

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2) Extended-spectrum penicillin

2.1. Ampicillin, Amoxicillin, Aminopenicillin
= administered orally
= has a broad-spectrum of activity
= highly active against gram positive and
gram negative bacteria
= acid-stable and B-lactamase sensitive

2.2. Carbenicillin and Ticarcillin
= both have broad spectrum activity
= active against gram negative bacteria
including (P. aeruginosa & Proteus)
= acid-stable
= not well tolerated by the intestine


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B. Cephalosporins
= isolated from fungus cephalosporium
= mechanism of action similar to penicillin in inhibiting
the transpeptidation reaction during peptidoglycan
synthesis
= all these drugs are derivatives of the 7-amino-
cephalosporamic acid
= contain a B-lactam ring structure similar to penicillin
= inactivated by B-lactamase
First Generation Cephalothin, Cefazolin and Cephalexin
bactericidal against most gram (+) bacteria

Second Generation Cefamandole, Cefuroxime and Cefaclor
bactericidal against gram negative bacilli

Third Generation Cefotaxime, Ceftazidime and Cefoperazone
less active against gram (+) but more active
against gram (-) bacteria

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C. Other B-lactam antibodies
= MOA similar to penicillin
= have a B-lactam ring and is resistant to B-lactamase

a) Monobactam - Aztreonam
= has excellent activity against aerobic gram (-)
organism such as the Enterobacteriaceae,
Pseudomonas, Gonococci and Hemophilus

b) Thienamycin - Carbapenem compounds
= active against all medically important organism
including organism frequently resistant to
other B-lactam antibiotics

c) B-lactamase inhibitors - Clavulamic acid, Sulbactam



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II. Cycloserine
= produced by specie of steptomyces
= broad-spectrum antibiotic used to treat patient with TB
= inhibit peptidoglycan synthesis

III. Vancomicin
= produced by specie of streptomyces
= used as alternative drug for serious infection in patient
who are allergic to B-lactam agents caused by
methicillin resistant S. aureus
= drug of choice for antibiotic-associated colitis
secondary to Cl. defficile infection

IV. Bacitracin
= polypeptide antibiotic produced by strain of B. subtilis
= bactericidal for many gram (+) organism and pathogenic
neisseria
= highly toxic: used for topical application only
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II. Protein Synthesis Inhibitors
= protein synthesis is the end results of 2 major processes
1) DNA dependent RNA synthesis (transcription)
2) RNA dependent protein synthesis (translation)
Inhibitors of transcription:
1) Actinomycin
= active against gram (+) and gram (-) bacteria as
well as mammalian cells
= toxic; with limited clinical use
2) Rifampicin
= are compounds which contain an aromatic ring
system
Rifampin = most useful member of the group
= effective against gram (+) organism
and mycobacteria
= major drug for the treatment of
tuberculosis, leprosy & as prophylaxis
against meningococcal meningitis

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Inhibitors of translation:
= translation of mRNA into protein are divided into 3
major phases

a) initiation - starts with association of mRNA in the 30s
ribosomal subunit to form a 30s initiation
complex

b) elongation - ribosome is the target site for protein
synthesis

c) termination of polypeptide chain -enzyme catalyzing
peptide formation (peptidyl transferase)


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Inhibitors of the 30s Ribosomal subunit:
1) Aminoglyside antibiotics
(Streptomycin, Neomycin, Kanamycin, Tobramycin)
Gentamicin and Amikacin
Streptomycin - bactericidal for gram (+), gram (-)
bacteria and M. tuberculosis
- drug of choice F. tularensis and
Y. pestis infection
Gentamicin, Tobramycin and Amikacin - active
against gram (-) bacteria incl. Pseudomonas
= synthesized by the genus streptomyces
= Gentamicin synthesized by micromonospora purpuriae
= MOA: binds to 30s ribosomal subunits and inhibit
protein synthesis
= may irriversively block initiation of translation or
cause mRNA misreading or both
= toxic and can cause renal and eight cranial nerve
damage, neuromuscular paralysis


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2) Tetracylines

= Oxytetracycline and Chlortetracycline,
Demethylchlotetracycline
= naturally produce by specie of the genus
streptomyces
= inhibit protein synthesis by combining with the 30s
subunits of the ribosome
= active against gram (+) and gram (-) bacteria
including Mycoplasma, Rickettsia and Chlamydia
= Semi-synthetic: Doxycycline, Minoccycline
- both are lipophilic and are absorbed completely
in the GIT

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3) Nitrofurans

Nitrofurantoin (synthetic derivative)
= used clinically to treat urinary tract infection
especially patient unable to tolerate
Sulfonamide

= most active against E. coli, Klebsiella,
Enterobacter and S. faecalis

= at present, it is recommended only for
uncomplicated UTI

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Inhibitors of the 50s Ribosomal Subunit:

1) Chloramphenicol
= produce from cultures of streptomyces venezuelae
= binds to the 23s RNA on the 50s ribosomal
subunits and inhibit peptide bond formation
(similar to erythromycin)
= bacteriostatic for gram positive and gram negative
bacteria including Rickettsia and Chlamydia
= maybe inactivated by the enzyme chloramphenicol
acetyltransferase which is carried by the R
plasmid
= very toxic, can cause allergic & neurotoxic reaction
= used only in serious and life-threathening situation
= most common side effect is bone marrow
depression leading to aplastic anemia and
decreased blood leukocytes


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2) Macrolide antibiotics (Erythromycin)
= synthesize by streptomyces erythraeus
= binds to the 50s ribosomal unit to inhibit peptide
chain elongation during protein synthesis
= most frequently used antibiotic in patient allergic
to penicillin
= primarily bacteriostatic, but may be bactericidal for
some organism
= effective against gram positive bacteria, mycoplasma
and few gram negative organism
3) Clindamycin / Lincomycin
= similar activity spectrum with Erythromycin but
chemically unrelated
= active against group A strept., Pneumococci and
Penicillinase producing staphylococci



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4. Puromycin
= not clinically useful but has an inhibiting effect on
growth of both procaryotic and eucaryotic
organism

5. Fusidic acid
= steroidal antibiotic with narrow antibacterial spectrum
= active against gram (+) bacteria
= no significant activity against gram (-) organism

Fucidin (salt of fusidic acid)
= used in the treatment of various serious
staphylococcal infection

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Inhibitors of Protein Assembly

Griseofulvin
= a fungistatic agent specific for fungi whose cell
wall contains chitin

= no effect on fungi with cellulose cell wall bacteria
and yeast

=given orally and clinically useful in treating chronic
dermatophyte infection


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Inhibitors of Tetrahydrofolate Synthesis (Folic acid synthesis)

1) Sulfonamide (analogue of PABA)

= generic name for derivatives of para-
aminobenzenesulfonamide or sulfanilamide
= first administered as a red dye Prontosil (Sulfanilanide)
= effective chemotherapeutic agent used systematically
as prevention and cure of bacterial infection in human
= MOA: interfere with synthesis of folic acid (required for
the synthesis of purine & pyrimedine) precursor of
RNA and DNA
= useful in the treatment of uncomplicated UTI



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2) Sulfones
= analogue of PABA and is most useful clinically
= derivatives of the diaminodiphenylsulfone (dapsone)
= primarily used to treat leprosy

3) Para-aminosalicylic Acid (PAS)
= highly specific for M. tuberculosis
= used primarily as a second-line drug in the treatment
of tuberculosis

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Inhibitors of dihydrofolate reductase

1) Trimethoprim

= antifolic acid agent
= very potent and a selective inhibitor of bacterial
dihydrofolate reductase
= spectrum of activity similar to sulfonamide
= are bactericidal and act synergistically with sulfonamide
or sulfamethoxazole
= useful in the treatment of recurrent or chronic UTI
and Pneumocystis infection
= also effective against bronchitis shigellosis and Ty fever


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2) Isoniazed (INH)
= hydrazide of isonicotinic acid
= highly specific for M. tuberculosis
= hepatotoxic
= most potent anti-TB drug
= never given as single drug

3. Flucytosine
= flourine analogue of cytosine
= an antifungal agent which is a true antimetabolite
= effective against most systemic deep-seated fungal
infection
= drug of choice for chromomycosis
= toxic effect: skin rashes, diarrhea, liver damage and
aplastic anemia

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III. Cell Membrane Inhibitors


1) Polymixin
= produced by Bacillus polymxa
= MOA: binds specifically to the outer surface of cell
membrane, altering their structure and osmotic
properties
= spectrum of activity is restricted to gram (-) organism
= reserved drug for the treatment of severe
Pseudomonas infection when organism is resistant
to other antibiotics
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2) Polyenes
= macrolide antibiotics, most important antifungal agent:
Amphotericin B and Nystatin
= MOA: binds to sterol in fungal membrane causing
disruption of membrane permeability resulting to
leakage of cell content
= active against yeast, fungi and other eucaryotic cells
but inhibitory to procaryotic organism
= selectively inhibit org. whose membrane contain sterols

Amphotericin B - cornerstone of antifungal therapy
= active agent most deep-seated fungi infection
= toxic and used only for serious life-threatening
infection

Nystatin - use to treat candida infection of the skin,
vagina and alimentary tract


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3) Azoles

3.1) Imidazoles: Ketaconazole, Miconazole, Clotrimazole
= acts by interfering ergosterol synthesis by the
fungal cell or disrupt fungal membrane
permeability and inhibit sterol synthesis
= blocks demethylation of ergosterol precursor
lanosterol
= broad-spectrum antifungal agent active against
dermatophytes, dimorphic fungi and yeast
= Miconazole and Clotrimazole are administered
topically only as a treatment of cutaneous
and vaginal candidiasis
= Ketoconazole given orally, very effective for
superficial and deep mycotic infection in
human

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3.2) Triazoles: Itaconazole, Fluconazole

= are substitute of imidazoles with antifungal
spectrum
= MOA same with Imidazole
= better tolerated when given orally
= effective in the treatment of deep mycoses
and opportunistic infection



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Inhibitors of DNA Function
= MOA: inhibit cross-linkage and intercalation between
the stacked bases of the double helix DNA
1) Mitomycin (synthetic antibacterial agent)
= converted enzymatically to a highly reactive
hydroquinone derivatives that acts as a bifunctional
alkalyting agent
= acts on the guanine residues of DNA and under certain
condition blocks the synthesis of host cell DNA

2) Quinolones
= all agents in the quinolone class are synthetic products
Nalidixic acid - first to be introduced as derivative of
naphthyridine compound
= blocks DNA replication
= bactericidal and use in the management of
uncomplicated UTI

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Newer Quinolones
Norfloxacin and Ciprofloxacin
= most useful flourinated compounds
= spectrum of activity includes Enterococci,
Staphylococci and Pseudomonas
Ciprofloxacin - most potent of the quinolones
= active against gram (-) and gram (+) bacteria
= used to treat UTI
3) Metronidazole
= effective antimicrobial agent for infection caused by
anaerobes and some protozoans
= no effect on facultative and aerobic organism

4) Novobiocin
= bactericidal especially among gram positive bacteria
= target site is the subunit B component of the DNA gyrase
= no valid therapeutic used at present