1. VICTORIA UNIVERSITY
BPHARM 2.2
PHARMACEUTICAL CHEMISTRY 1
GROUP 1 PRESENTATION APRIL 2024
QUESTION
Classify with examples the different antibiotics under aminoglycoside Mechanisms of action for
aminoglycoside
The different antibiotics’ pharmacological/therapeutic indications. Draw and name the structures of
each aminoglycoside
Structural elucidation
Chemical synthesis
Structural activity relationships (SARs) and structural variations for aminoglycoside
2. PRESENTED BY
• AYEBARE JACOB
• BARUHO JULIUS
• BBOSA TOM
• MAATO ROBERT
• AINOMUGISHA PAMELLA
• SSANYU VIOLET
• SARAH FONI JOHN
• VU-BPC-2209-1396-DAY
• VU-BPC-2209-0419-DAY
• VU-BPC-2209-1044-DAY
• VU-BPC-2301-0070-DAY
• VU-BPC-2209-0843-DAY
• VU-BPC-2301-0074-DAY
• VU-BPC-2301-0724-DAY
5. Cont….
• This nomenclature system is not specific for
aminoglycosides. For example vancomycin is a
glycopeptide antibiotic and erythromycin, which is
produced from a species of Saccharopolyspora (which
was previously misclassified as Streptomyces) along with
its synthetic derivatives clarithromycin and azithromycin
are macrolides - all of which differ in In their MOA.
8. STRUCTURE
• Amino sugars linked through glycosidic bonds
• Aminoglycosides have a hexose ring (1,3 Diamino-
cyclohexane) either streptidine (in streptomycin) or
2deoxystreptamine (other aminoglycosides), to
whichvarious amino sugars are attached by glycosidic
linkages.
11. Classification
On source basis
Aminoglycosides that are derived from bacteria of the
Streptomyces genus are named with the suffix -mycin,
while those which are derived from Micromonospora
are named with the suffix -micin.
15. Classification: (Route of administration:
A. Aminoglycosides used through IM route
1. Streptomycin
B. Aminoglycosides used through IM/IV route
1.Gentamicin
2.Tobramycin
3.Netilmicin
4. Amikacin
5. Kanamycin 6. Sisomicin
19. MOA of aminoglycosides
• Irreversibly bind at 30S subunit of bacterial ribosome
interfering with the attachment of mRNA
• Interfere with the formation of the initiation complex.
• They cause misreading of mRNA,leading to
incorporation of of incorrect AA,in the growing
polypeptide chain
21. cont
• They cause premature termination of translation.
• NB.aminoglycosides are absorbed into the gram-ve
bacterial membrane by an oxygen dependent active
transport mechanism.
• As a result, aminoglycosides are ineffective against
anaerobic bacteria
• They have a synergistic effect with beta-lactam
antibiotics eg penicillins
23. Spectrum
• Narrow spectrum
– Aerobic gram negative bacilli
– Not effective against
• gram positive cocci & bacilli
• gram negative cocci
• and anaerobes
25. Pharmacokinetics
• Highly polar drugs
– very poor oral bioavailability
– hence given I.V. or I.M.
– Rapid absorption from i.m. sites.
• Poorly distributed and poorly protein bound
– P/E - fail to reach intraocular fluid, or CSF,
– Highly polar drugs
26. Pharmacokinetics
• Gentamycin - cross BBB in meningeal
inflammation.
– Can be used in cerebral meningitis.
• Excreted through kidney, unchanged
• All are more active at alkaline pH than acidic.
28. Antibacterial resistance
Three principal mechanisms for the development of resistance:
• Synthesis of plasmid mediated bacterial transferase enzymes that can
inactivate aminoglycosides.
• Mutation/deletion of porin channels resulting in decreased transport
of aminoglycoside into the bacterial cytosol.
• By deletion or alteration of the receptor protein on 30S (Target)
ribosomal unit because of mutations. Attachment of drug with 30S
ribosomal unit is thus prevented.
31. Ototoxicity
• Accumulate in the endolymph and perilymph
of inner ear
• Vestibular/cochlear sensory cells & hairs undergo
concentration dependent destructive changes.
• leading to vestibular and cochlear damage which
is irreversible.
32. Ototoxicity
• Dose & duration of treatment related adverse
effect
• Drugs concentrated in labrinthine fluid, slowly
removed as plasma levels fall.
• Ototoxicity greater when plasma levels are
persistently high.
33. Ototoxicity
• Old patients more susceptible.
• Vestibular toxicity is more with Streptomycin
& Gentamycin
• Cochlear toxicity is more with
neomycin & amikacin.
34. Nephrotoxicity
• Attain higher concentration in the renal cortex
• Manifests as tubular damage resulting in
– loss of urinary concentrating power
– low g.f.r.
– nitrogen retention
– albuminuria & casts.
35. Nephrotoxicity
• More in elderly & patient with pre-existing renal disease.
• Totally reversible (PCT cells regenertae )provided drug is promptly
discontinued.
• An important implication of aminoglycoside induced nephrotoxicity is
– reduced clearance of antibiotic
– higher blood levels
– enhanced Ototoxicity.
38. Nephrotoxicity
• Intrapleural/intraperitoneal instillation of
large doses of AG
Reaction can follow after i.v, im, oral
• Association with anaesthesia
• Co-administration of other NM blocking
agents
• Patients with Myasthenia gravis particularly
susceptible to NMB by AG
40. Precautions & Interactions
• Pregnancy – risk of foetal ototoxicity
• Patients past middle age; compromised renal functions.
• Patients with kidney damage
• Avoid concurrent use of
Ototoxic drugs minocycline & high ceiling diuretics
Nephrotoxic drugs amphotericin B, vancomycin, cyclosporin & cisplatin
Muscle relaxants.
• Do not mix it with any drug in the same syringe/infusion bottle.
42. Indications of gentamycin
• UTI caused by sensitive bacteria eg Pseudomonas aeruginosa,E.coli
• RTI caused by sensitive bacteria eg Klebsiella pneumoniae and
• Systemic infections caused by G-ve bacteria eg E.coli, Klebsiella
pneumoniae, Enterobacter spp, Pseudomonas aeruginosa
• Bone and tissue infection
• Eye infections
43. Indications of amikacin
• Mainly used in the treatment of nosocomial infections resistant to gentamycin eg
RTI,UTI,septiceamia and intrabdominal infections
• Caused by gram –ve bacteria eg E.coli,Klebsiela spp,Pseudomonas
aeruginosa,enterobactor spp etc
• Treatment of bone and joint infections caused by susceptible organisms
• Treatment of skin and soft tissue infections caused by susceptible organisms
• Treatment of endocarditis in combination with other anti-biotics
• Treatment of drug resistant cases of TB(active against mycobacterium tuberculosis)
in combination with other antibiotics
44. Indications of kanamycin
• Treatment of MDR TB in combination with other antibiotics
• RTI
• UTI
• Intrabdominal infections
• Bone and soft tissue infections
• Septicemia
• Meningitis caused by susceptible organisms
• Preoperative prophylaxis especially in abdominal and urogenital procedures
45. Indications of streptomycin
• Its active against mycobacterium tuberculosis
• Treatment of brucellosis( its active against
Brucella spp)
• Bacterial endocarditis caused by susceptible
bacteria
46. Indications of Neomycin
• This drug is too toxic for parenteral administration
• It is only used for skin infections or mucus
membranes eg in Gynanfort vaginal pessaries,
neomycin sulphate cream
• Used to reduce bacterial population of the colon
prior to bowel surgery
47. Neomycin
• Wide spectrum
• Highly Cochlear Toxic, and Nephrotoxic
• Most common use is topical, ointment, eye and ear drops
– ( in combination with Polymyxin, Bacitracin as Nebasulf,
Polybiotic cream, etc)
• Neomycin with Polymyxin-B solution is used as an
irrigant in urinary bladder to prevent bacteriuria
associated with use of indwelling catheter.
48. Oral neomycin has damaging effect on intestinal villi-
Malabsorption syndrome.
Damages colonic flora- deficiency of vit. K
Superinfection
Not used systemically ( Except for preparation of bowel
for surgery and in Hepatic Coma or Hepatic
Encephalopathy)
49. Indications of tobramycin
– Its more active against Pseudomonas aeruginosa than
gentamycin
– Treatment of bacterial conjunctivitis. It may be
combined with dexamethasone eg Tobradex eye drops
– Treatment of LRTI
– Treatment of Intra-abdominal infections
50. cont
– Treatment of skin infections
– Treatment of recurrent UTI
– Treatment of cystic fibrosis in the lungs caused by Pseudomonas
Aeruginosa.(in inhalation form)
• NB
• Gentamycin ,tobramycin and amikacin are active against
Pseudomonas aeruginosa
51. Netilmicin
• As it is not metabolised by aminoglycoside inactivating
enzymes so active against bacteria resistant to
gentamycin
52. Framycetin
• Same as neomycin
• Too toxic for systemic administration
• Used topically on skin, eye, ear in the same manner as neomycin
Soframycin
1% skin cream,
0.5% eye drops or ointments
53. Structural Activity Relationship(SAR) and structural
variations in Aminoglycosides
SAR of a drug refers to the relationship its
chemical structure and biological activity
54. Aminoglycosides
• Aminoglycosides inactivating enzymes include;
• Aminoacetyltransferases (ACC) which acetylate the 6’-NH2 of
ring I ,the 3-NH2 of ring II or the2’NH2 of ring 1
• Phosphotransferases (APH) which phosphorylate the 3’-OH of
ring I or the 2’-Ohof ring III
• Nucleotidyltransferases (ANT) which adenylate the 2’-OH of ring
III, the 4’-OH of ring I or the 4’-OH of ring I or the 4’OH of ring III
56. SARs
• It is convenient to discuss aminoglycoside SARs in terms of substituents in
rings I,II and III
• Ring I is crucially important for characteristic broad spectrum antibacterial
activity and it is also the primary target for bacterial inactivating enzymes
• Amino functions at 6’ and 2’ are important as Kanamycin B(6’-amino,2’-
amino) is more active than Kanamycin A(6’-amino,2’hydroxyl) which in
turn is more active than Kanamycin C(6’-hydroxyl,2’-amino)
57. Conti..
• Methylation at either the 6’carbon or the 6’-
amino positions does not lower anti bacterial
activity and confers resistance to enzymatic
acetylation of the 6’-amino group.
• Removal pf the 3’-hydroxyl or 4’-hydroxyl
group or both in the kanamycins (e.g 3’4-
dideoxykanamycin B or dibekacin) does not
reduce anti bacterial activity
58. Conti..
• The gentamicins also lack oxygen functions at these positions as do
sisomicin and netilmicin which also have a 4’,5’-double bond.
• None of these derivatives is inactivated by phosphotransferase
enzymes that phosphorylate the 3’-hydroxyl group.
• Evidently ,the 3’phosphorylated derivatives have very low affinity
for aminoglycoside-binding sites in bacterial ribosomes.
59. Ring II
• Few modifications of Ring II functional groups are possible without appreciable
loss of activity in most of the aminoglycosides.
• The 1-amino group Kanamycin A can be acylated (e.g amikacin), however with
activity largely retained. Netilmicin(1-N-ethylsisimicin) retains the antibacterial
potency of sisomicin and is resistant to several additional bacteria-inactivating
enzymes 2’’-hydroxysisomin is claimed to be resistant to bacterial strains that
adenylate the 2’’-hydroxyl group of ring III
• Whereas 3-deaminosisomicin exhibits good activity against bacterial strains that
elaborate 3-acetylating enzymes.
60. Ring III
• Ring III functional groups appear to be less sensitive to
structural changes than those of Ring I and Ring II.
• Although the 2’’-deoxygentamicins are significantly less
active than their 2’’-hydroxyl counterparts, the 2’’-amino
derivatives(seldomycins) are highly active
• The 3’’-amino group of gentamicins may be primary or
secondary with high antibacterial potency
61. Conti..
• The 4’’-hydroxyl group may be axial or
equatorial with little change in potency
• The discovery of agents with higher
potency/toxicity ratios remains an important
goal of aminoglycoside research.
62. Amikacin
Aminoglycosides, including amikacin, share a core structure that
typically consists of two or more amino sugars connected by glycosidic
bonds to an aminocyclitol ring (most often a 2-deoxystreptamine ring).
This core structure is crucial for binding to the bacterial 30S ribosomal
subunit, interfering with protein synthesis, which ultimately leads to
bacterial death
64. Conti..
• Amikacin is chemically modified from its parent compound, kanamycin A, to
enhance its antibiotic activity and resistance to enzymatic degradation.
• Specifically, amikacin has a L-(-)-γ-amino-α-hydroxybutyryl (L-HABA) group
attached to the 1-N position of the 2-deoxystreptamine ring. This modification
is significant for several reasons:Resistance to Enzymatic Degradation:
• The L-HABA group makes amikacin resistant to most aminoglycoside-
modifying enzymes produced by resistant bacteria. These enzymes typically
inactivate aminoglycosides by phosphorylation, adenylylation, or acetylation.
65. Conti..
• Aminocyclitol Ring: The presence and specific orientation of functional
groups on the aminocyclitol ring are crucial for ribosomal binding and
antibacterial activity. Modifications on this ring can significantly impact
drug potency and spectrum of activity
• .Amino Sugars: The number and position of amino sugars, along with
their specific glycosidic linkages, play a critical role in determining the
drug's affinity for the bacterial ribosome and its susceptibility to
enzymatic inactivation.
67. Conti..
• Gentamicin is a complex mixture of closely related compounds
(gentamicins C1, C1a, C2, C2a, and C2b are the major components) each
differing slightly in structure but working synergistically for antibacterial
activity
• The core structure of aminoglycosides, including gentamicin, consists of
an aminocyclitol ring (2-deoxystreptamine in most cases) linked to
amino sugars via glycosidic bonds. This core is essential for the drug's
ability to bind to the bacterial ribosome
68. Structural variations
• The variations among the different components of gentamicin
mainly involve differences in the number and position of hydroxyl
(-OH) and amino (-NH2) groups on the amino sugars, as well as
variations in the sugar moieties themselves.
• These structural differences, while subtle, can influence the drug's
affinity for the bacterial ribosome, its spectrum of activity, and its
susceptibility to enzymatic degradation by bacterial enzymes.
69. Contin..
• Aminocyclitol Ring: The presence of the aminocyclitol ring is fundamental for
binding to the ribosomal RNA. Modifications in and around this ring can
significantly impact the drug's binding affinity and its bactericidal efficacy.
• Amino Sugars: The nature (e.g., methyl or hydroxyl groups) and positioning of
substituents on the amino sugars influence the drug’s ability to evade
bacterial modifying enzymes, which are a common resistance mechanism.
For example, specific modifications can make aminoglycosides more resistant
to acetyltransferases, phosphotransferases, and nucleotidyltransferases..
70. Conti..
• Glycosidic Bonds: The orientation and sequence of glycosidic bonds
connecting the amino sugars to the aminocyclitol ring are critical for
maintaining the three-dimensional structure necessary for binding to the
ribosome. Alterations here can disrupt binding or change the drug's
susceptibility to enzymatic degradation
• Hydroxyl Groups: The number and placement of hydroxyl groups on
gentamicin molecules affect not only their solubility but also their resistance
to enzymatic inactivation and their affinity for the bacterial ribosome
72. Conti..
• streptomycin contains a streptidine moiety linked to two sugars, N-methyl-
L-glucosamine and streptose, forming a trisaccharide structure. This unique
structure contributes to its distinct mode of action and spectrum of activity
• Streptidine Moiety: The presence of the streptidine moiety, a guanidine-
containing cyclohexane, is critical for the antibacterial activity of
streptomycin.
• The guanidine group is believed to form key hydrogen bonds with the 16S
rRNA of the bacterial 30S ribosomal subunit, disrupting protein synthesis
73. streptomycin
• N-methyl-L-glucosamine: This sugar is essential for binding to the
ribosome. Modifications to this part of the molecule can significantly
impact the drug's ability to inhibit protein synthesis.
• Streptose Sugar: The streptose sugar is important for the orientation of
streptomycin when it binds to the bacterial ribosome. Alterations to the
streptose could affect the antibiotic's efficacy.
• structural modifications to streptomycin are not commonly pursued due
to its unique structure and mechanism
75. Conti..
• Core Structure: The core structure of neomycin molecules
includes two deoxystreptamine rings linked to multiple sugar
moieties.
• This bivalent nature is critical for the drug's ability to bind
tightly to the ribosomal RNA, disrupting protein synthesis
effectively
• Amino Sugars: The presence and positioning of amino sugars
are key determinants of neomycin's activity.
76. Conti..
• Glycosidic Bonds: The specific glycosidic linkages between
the sugars and the aminocyclitol rings significantly influence
the stability of the antibiotic and its resistance to enzymatic
degradation.
• This stability is crucial for maintaining the antibiotic's
efficacy against bacteria that produce enzymes capable of
inactivating aminoglycosides
77. Neomycin structural variations
• Neomycin B vs. Neomycin C: The primary difference between neomycin
B and C is the substitution at the 6' position on the ring. Neomycin B has
a hydrogen, whereas neomycin C has a hydroxyl group.
• This slight variation affects the antibiotic's solubility and potency, with
neomycin B generally being more active.Neamine (Neomycin A):
Neamine, the least complex of the three, lacks some of the sugar
moieties present in B and C but serves as the foundational structure
from which the other two are derived.
