Brief explanation about chemotherapy

2. Anti-microbial agents: which may be natural, semi-synthetic
and synthetic compounds and they are used to kill and inhibit
the growth of microbes.
Cidal: An agent which kill the microbes.
Eg: Bactericidal
Fungicidal
Viricidal
Static: An agent which inhibits the growth of microbes.
Eg: Bacteriostatic

3. History
• Anti-microbial use is to have been common practice
for at least 2000 years.
• Ancient Egyptians and ancient Greeks used specific
molds and plant extracts to treat infections.
• In 19th century, microbiologists such as Louis Pasteur
and Jules Francois Joubert observed antagonism
between some bacteria and discussed the merits of
controlling these interactions in medicine.

4. Some of the anti-microbial agents are:
• β-lactams
• Aminoglycosides
• Quinolones
• Macrolide antibiotics

5. β – lactam antibiotics
I. Penicillin's
a) Narrow spectrum antibiotics
E.g. penicillin G
penicillin V
b) Penicillinase-resistant penicillin's
E.g. Methicillin
Nafcillin
c) Extended- spectrum penicillin's
E.g. Ampicillin
Amoxicillin

6. In 1928, Alexander Fleming became the first to discover a
natural anti-microbial fungus known as Penicillium
rubens and named extracted substance penicillin which in
1942 was successfully used to treat a streptococcus
infection.
Chemistry
• Penicillins are subsistuted with 6- aminopencillinaic
acids.
• A thiazolidine ring is substituted to beta-lactam ring that
carries a secondary amino group.
• Substituents can be attached to the amino group.
• Structural integrity of the 6-amino penicillanic acid
nucleus is essential for the biologic activity of these
compounds.

8. Mechanism of action
• Penicillins like β- lactam antibiotics, inhibit bacterial
growth by interfering with specific step in bacterial
cell wall synthesis.
• Cell wall maintains the shape of the cell and prevent
cell lysis that would occur as a result of the high
osmotic pressure in the cell.

10. • Cell wall is composed of a complex cross polymers,
peptidoglycan consisting of polysaccharides and
polypeptides.
• The polysaccharide contains altering amino-sugars,
N-acetyl-glucosamine and N- acetyl-muramic acid.
• A 5-aminoacid peptide is linked to the N-
acetylmuramic acid sugar. This peptide terminates in
D-alanyl-D-alanine.
• β- lactam antibiotics are structural analogues of the
natural D-alanyl-D-alanine substrate and they are
covalently bound by Pencillin Bound Proteins (PBPs)
at the active site.

11. • PBPs catalyze the transpeptidase reaction that
removes the terminal alanine to form a cross link with
a nearby peptide, which gives cell wall and its
structural rigidity.
• After a β-lactam antibiotic has attached to the PBP,
the transpeptidation reaction is inhibited,
peptidoglycan synthesis is blocked, and the cell dies.

12. Adverse effects
• Hypersensitivity reactions
• Severe Hypotension
• Jarisch-Herxheimer reaction
• Diarrhoea
• Congestive cardiac failure

13. Cephalosporins
• First generation
E.g Cephalexin
Cephradine
Cefadroxil
• Second generation
E.g. Cefuroxime
Cefotiam
• Third generation
E.g. Ceftibuten
Cefexime
• Fourth generation
E.g. Cefclidine

14. • Cephlosporins are similar to penicillins chemically, in
mechanism of their action and in adverse effects.
• Except the first generation drugs, rest are most
resistant to β-lactamase degradation and therefore
have a broader sprectum of activity against gram-
negative bacteria compared to penicillins.

15. Mechanism of action
• Cephalosporin's inhibit the transpeptidation process
leading to the formation of imperfect cell wall.
• Osmotic drive from outside isotonic environment of
the host to the inside of the hypertonic bacterial
cytoplasm and finally activation of the autolysin
enzyme leading to the lysis of bacteria.
• Hence the cephalosporin's are also bactericidal drugs.

16. Adverse effects
• Hypersensitivity
• Gastrointestinal disturbances
• Nephrotoxicity
• Severe bleding

17. Carbapenems
E.g. Imipenem
• Carbapenems, acts by inhibiting bacterial cell wall
synthesis and produces bactericidal activity.
• It has a wide spectrum of anti-bacterial activity
against gram +ve organisms like
streptococci,staphylococci,enterococci.
• Gram –ve organisms like P.aeruginosa and entero
bacteriaceae.

18. Intravenous imipenem
via glomerular filteration
in renal tubule
cilastatin - dehyropeptidase
Rapid hydrolysis of imipenem
Excerted in urine

19. Monobactams
E.g. Aztreonam
• Monobactams acts by inhibiting the bacterial cell wall
synthesis.
• It is effective only against gram –ve bacteria, such as
Enterobacteriaceae, P. aeruginosa, gonococci but has
no activity against gram +ve bacteria and anaerobes.

20. Resistance
Resistance to penicillins and other beta-lactams
are due to four general mechanisms.
I. Inactivation of antibiotic by beta-lactamase.
II. Modification of target PBPs.
III. Impaired penetration of drug to target PBPs.
IV. Presence of an efflux pump.
Inactivation of antibiotic by beta-lactamase.
• Beta-lactamase production is most common
mechanism of resistance.

21. • More than 100 different beta-lactamases have been
identified.
• Some of them are produced by staphylococcus
aureus, haemophilus species and E.coli are relatively
narrow in substrate specificity and will hydrolyse
penicillins but not cephalosporins.
• Some other beta-lactamases are produced by
Pseudomonas aeruginosa and Enterobacter species
are much broader in spetrum and will hydrolyse both
cephalosporins and penicillins.
• Carbapenems, which are highly resistant to
hydrolysis by penicillinases and cephalosporinases
are hydyolysed by metallo beta-lactamase.

22. Modification of target PBPs
• Altreation in target PBPs (penicillin bound proteins)
is responsible for methicillin resistance and penicillin
resistance in pneumococci.
• These resistant organisms produce PBPs that have
low affinity for binding beta-lactam antibiotics, and
as a result they are not inhibited except at relative
high drug concentrations.

23. Impaired penetration of drug to target PBPs
• Resistance caused by impaired penetration of
antibiotics to target PBPs, which occurs only in gram
–ve species, is due to impermeability of the outer
membrane that is present in gram –ve bacteria not in
gram +ve bacteria.
• Beta-lactam antibiotics cross the outer membrane and
enter gram –ve organisms via outer membrane protein
channels.
• Absence of the proper channel or down regulation of
its production can prevent or greatly reduce drug
entry into the cell.

24. Presence of an efflux pump
• Gram –ve organisms also may produce an efflux
pump, which consists of cytoplasmic and periplasmic
protein components, that efficiently transport some
beta-lactam antibiotics from the periplasm back
across the outer membrane.
E.g. Extrusion of nafcillin by salmonella typhimurium.

25. Aminoglycosides
Drugs
Streptomycin
Gentamicin
Tobramycin
Amikacin
Kanamycin
Sisomicin
Neomycin

27. Mechanism of action
Aminoglycosides are bactericidal agents- inhibit
protein synthesis.
Entry of aminiglycosides into bacterial cell
Bind to 30s ribosomal subunit
Inhibit initiation of Cause misreading of
Protein synthesis codon

28. cause misreading of codon
Premature termination of Insertion of wrong amino
Protein synthesis acid into the growing
peptide chain
Formation of defective proteins
Incorporation of defective proteins into bacterial cell
membrane
Altered permeability and distruption of cell membrane

29. Resistance
Bacterial resistance to aminoglycosides is due to
I. Inactivation of the drug by bacterial enzymes
The microorganism produces a transferase
enzyme or enzymes that inactivate the
aminoglycoside by adenylation, acetylation or
phosparylation.
II. Decreased entry of drug into bacterial cell
Impaired entry of aminoglycoside into the cell.
This may be genotypic; i.e, resulting from mutation
or deletion of a porin protein or proteins involved in
transport and maintainance of the electrochemical
gradient.

30. III. Decreased affinity of the drug for the ribosomes.
The receptor protein on the 30s ribosomal
subunit may be deleted or altered as a result of a
mutation.
Adverse effects
• Ototoxicity
• Nephrotoxicity
• Neuromuscular blocking effect
• Hypersensitivity reactions

31. Quinolones
• The first quinolone, naldixic acid, is a urinary
antiseptic.
• It is effective against garam –ve bacteria including
E.coli, Proteus, Klebsiella, Enterobacter, Salmonella,
Shigella, but not Pseudomonas.
• Nalidixic acid inhibits DNA gyrase enzyme and
interferes with the replication of bacterial DNA.
• It is useful in the treatment of uncomplicated UTI due
to gram –ve bacteria and diarrhoea due to shigella or
salmonella.

33. Mechanism of action
DNA gyrase (topoisomerase II) Topoisomerase IV in
in gram –ve bacteria gram +ve bacteria
Nicking, formation of –ve Nicking and seperation
Supercoils and resealing of of daughter DNA strands
Strands of DNA following DNA
replication

34. Resistance
• During fluroquinolone therapy, resistant organisms
emerged especially among Staphylococci,
pseudomonas and serratia.
• Resistance is due to 1 or more point mutations in the
quinolone binding region of the target enzyme or to
change in the permeability of the organism.
• DNAgyrase is the primary target in E.coli with the
single step mutants exhibiting amino acid substitution
in the A subunit of gyrase.
• Topoisomerase IV is a secondary target in E.coli that
is altered in mutants expressing higher levels of
resistance.

35. Adverse effects
• Hemolytic anemia
• Mild CNS disturbances
• Mild GIT distrubances

36. Macrolide antibiotics
• Erythromycin was obtained by Streptomyces
erythreus.
• Erythromycin was active against S. pneumonia, S.
pyogenes.
• Roxithromycin, clarithromycin and azithromycin are
the semisynthetic macrolides.
Mechanism of action
• Macrolides inhibit the protein synthesis by binding
reversibly to the P-site of the 50s ribosomal subunit
of the bacteria.

38. • Precisely, these drugs inhibit the translocation step
where in t-RNA with its growing peptide chain is
translocated from the A- site to P- site.
• As a result, the ribosome cannot move on one codon
furthur towards right, relative to m-RNA.
• In otherwords, the A site does not become free to
accept the next incoming t-RNA charged with desired
aminoacid.
• The protein synthesis thus stops.

39. Resistance
Resistance to macrolides is usually plasmid
encoded.
Three mechanisms have been identified.
i. Reduced permealibity of the cell membrane or
active efflux.
ii. Production of esterases that hydrolyze the
macrolides.
iii. Modification of the ribosomal binding site by
chromosomal mutation or by a macrolide-
induciable or a constitutive methylase.

40. • Efflux and methylase production account for the vast
majority of cases of resistance in gram –ve organism.
• Cross- resistance is complete between erythromycin
and the other macrolides.
• Constitutive methylase production also confers
resistance to structurally unrelated but
mechanistically similar compounds such as,
clindamycin and streptogram B would share the same
ribosomal binding site.
• Because non- macrolides are poor inducers of the
methylase, strains expressing an induciable methylase
will appear susceptible invitro.

41. • However, constitutive mutants that are resistant can
be selected out and emerge during therapy with
clindamycin.
Adverse effects
• Gastro-intestinal effects
• Liver toxicity
• Drug-Interactions
Erythromycin increases serum concentrations of oral
digoxin by increasing its bioavaliability.

42. References
• G. katzung 8th edition
• Sharma and sharma
• K.D Tripathi 8th edition