Antibacterial chemoterapeutics 2
1.β-lactame antibiotics
1.1Penicillins
1.2 Cephalosporins
2. Macrolide antibiotics
3.(Poly)peptide antibiotics
4. Aminoglycoside antibiotics
©assoc. prof. PharmDr. Oldřich Farsa, Ph.D. 2012
β-lactame antibiotics
Lactams = internal amides of amino acids
OH
O
NH2
N
H
O
N
H
O NH
ON
H
O
t
+ H2O
αβ
α
α
β
β
β
α
γ
γ
γ
δ
δ
ε
ε
α
β
γ
δ
6-aminohexanoic acid
ε-aminocaproic acid
azepan-2-on
ε-caprolactam
6-hexanlactam
piperidin-2-on
δ-valerolactam
5-pentanlactam
pyrrolidin-2-on
γ-butyrolactam
4-butanlactam
azetidin-2-on
β-propiolactam
3-propanlactam
β-lactame antibiotics
N
S
O
N
H
CH3
CH3
OH
O
H
H
H
R
O
N
S
O
N
H
O OH
HH
O CH3
O
R
O
Penicillins
N-acyl-6-aminopenicillanic acids
Cephalosporins
N-acyl-7-aminocephalosporanic acids
Mechanism of action
• inhibition of cell wall synthesis by binding to specific proteins
Penicilins
History
World
1928(9) – Alexander Fleming – isolated a liquid concentrate inhibiting
growth of bacteria from a mould of Penicillium species
1939 - 1943 Fleming, Florey, Chain & Johnson – isolation and constitution
of penicillins
1945-Nobel prize for Fleming, Florey and Chain
Czech territory
1943 – Málek, Fragner, Herold, Hais etc. – Mykoin BF 510
Penicillins
The initial „amorphous penicillin“ was a mixture of several compounds:
N
S
O
N
H
CH3
CH3
OH
O
R
O
H
H
H
CH3
C
H2
C
H2
C
H
C
H
C
H2
C
H2
OH
CH3
C
H2
C
H2
C
H2
C
H2
C
H2
CH3
C
H2
C
H2
C
H2
C
H2
R Penicillin
pentenyl- F
benzyl- G
p-hydroxybenzyl- X
heptyl- K
amyl- dihydro-F
Penicillins
Benzylpenicillin and its problems
N
S
O
N
H
CH3
CH3
OH
O
O
H
H
H
benzylpenicillin
syn. penilcilin G
• production of benzylpenicillin by the mould ↑ by addition of phenylacetic acid into its broth
Problems:
• weak binding to plasmatic proteins ⇒ fast excretion ⇒ frequent administration is necessary
• instability in acid media of stomach (see reaction scheme) ⇒ impossibility of p.o. application
N
S
O
N
H
CH3
CH3
OH
O
O
H
H
H
H
+
NH
S CH3
CH3
OH
O
H
H
N
OO
S CH3
CH3
OH
O
H
H
N
N
OOH
benzylpenicillin penillic acid
Penicillins
Benzylpenicillin and its problems
3. Sensitivity to penicillinases (β-lactamases – enzymes catalysing hydrolytic
cleavage of the β-lactame ring ) – see the scheme
N
S
O
N
H
CH3
CH3
OH
O
O
H
H
H
NH
S
O
N
H
CH3
CH3
OH
O
O
H
H
H
OH
β − lactamase
H2O
benzylpenicillinic acid
4. Rel. narrow spectrum – only G+
strains (Streptococcus, Staphylococcus,
Clostridium, Neisseria, Corynebacteriun, Bacilus anthracis …)
5. Inducing allergies – anaphylactic shock – caused by 6-aminopenicillanic acid as
the impurity – resolved by better purification (chromatography)
Penicillins
Resolving of benzylpenicillin problems
Ad 1. (necessity of frequent application) – poorly soluble salts with
organic bases
N
S
O
N
H
CH3
CH3
O
OO
H
H
H
N
S
O
N
H
CH3
CH3
O
OO
H
H
H
NH2
+
NH2
+
N
S
O
N
H
CH3
CH3
O
OO
H
H
H
CH3
N
+
CH3
O
NH2
O
benzathine benzylpenicillin
Pendepon®
inj. sic.
procaine benzylpenicillin
Prokain Penicilin G®
Biotika inj. sic.
•depot (= long acting) forms for i.m. injections
Penicillins
Resolving of benzylpenicillin problems
Ad 2. – ↑ of stability in acid media
N
S
O
N
H CH3
CH3
OH
O
O
O
H
H
H
phenoxymethylpenicillin
syn. penicillin V
• acquired by addition of phenoxyacetic acid into the broth of the production strain
• suitable for p.o. administration
V-Penicilin®
, Ospen®
Penicillins
Overall resolving of benzylpenicililn problems – semi-synthetic penicillins
•penicillinamidase (penicillinacylase) – hydrolyzes acyclic amide bond, not βlactame
ring
•used a microbe which produces it (e.g. E. coli)
N
S
O
N
H
CH3
CH3
OH
O
O
H
H
H
N
S
O
NH2 CH3
CH3
OH
O
H
H
H
O
OH
N
S
O
NH2 CH3
CH3
OH
O
H
H
H
R Cl
O
R O R
O O
N
S
O
N
H
CH3
CH3
OH
O
H
H
H
R
O
penicillinamidase
(H2O)
+
6-aminopenicillanic acid phenylacetic acid
a semi-synthetic penicillin
Penicillins
Mostly semi-synthetic penicillins stable in acid media
•stability against acids is increased by electron-donor substituents in N-acyl side
chain (I+ or M+ efekt)
N
S
O
N
H
CH3
CH3
OH
O
O
H
H
H
NH2
N
S
O
N
H CH3
CH3
OH
O
O
O
H
H
HR
ampicillin
Ampicilin ®
cps., inj sic.
R = -H phenoxymethylpenicillin
V-Penicilin®
tbl., Ospen tbl. obd.
R = -CH3 phenethicillin
R = -CH2CH3 propicillin
Penicillins
Semi-synthetic penicillins resistant to β-lactamases
•formed by acylation of amino group of 6-aminopenicillanic acid with bulky
acyl rest; the lactame ring is then sterically hindered (⇒ protected)
O
CH3
O
CH3
N
S
O
N
H
CH3
CH3
OH
O
O
H
H
H
N
S
O
N
H
CH3
CH3
OH
O
O
H
H
H
O
N
CH3
R
1R
2
meticillin
R1
= R2
= -H oxacillin
Prostaphlin®
cps., inj. sic.
R1
= -Cl, R2
= -H cloxacillin
R1
= R2
= -Cl dicloxacillin
R1
= -Cl, R2
= -F flucloxacillin
syn. floxacillin [USAN]
●resistant also to acid media; the resistance increases
oxacillin < cloxacillin < dicloxacillin = flucloxacillin
Penicillins
An alternative approach to ↑ of resistance to β-lactamases:
β-lactamases inhibitors
●
compounds with β-lactam ring which binds to the enzyme active site with greater
affinity and block this site
●used in combination with penicillins
N
O
O
OH
O
OH
H
N
S
O
O
O
CH3
CH3
OH
O
H
N
S
O
O
O
CH3
OH
O
H
N N
N
clavulanic acid
●isolated from Streptomyces
clavuligerus
+ amoxicillin (= Amoxiklav®
,
Augmentin®
)
+ ticarcillin (= Timentin®
inj. sic.)
4,4-dioxopenicillanic
acid
sulbactam
Betrion®
+ ampicillin (=
Ampisucillin®
inj. plv.
sol.)
tazobactam
+ piperacillin (=
Tazocin®
inj. sic.)
Penicillins
A combination of a penicilline with a β-lactamase inhibitor in one molecule
N
S
O
NH
CH3
CH3
O
O
O
O
NH2
O
N
S
CH3
CH3
O
O
O
•a mixed ester of ampicillin and sulbactam with methanediol
•a prodrug of both components
sultamicillin
Bitamon®
inj. sic., Unasyn®
tbl. obd.
Penicillins
Penicillins with broadened spectrum
Ad 4. – introduction of a hydrophilic substituent to α-position of the acyl attached to
amino group of 6-aminopenicillanic acid ⇒ broadening of the antibacterial spectrum
of penicillins also to G-
strains
Compouns with free primary amino group
N
S
O
N
H
CH3
CH3
OH
O
O
H
H
HNH2
R
N
S
O
N
H
CH3
CH3
OH
O
O
H
H
HNH2
R = -H ampicillin
R= -OH amoxycillin
Amoclen®
, Amopen®
epicillin
Penicillins with broadened spectrum
Ampicillin prodrugs
H
NH
O
H
NH2
H
S
H
N
O
H
CH3
O
O
CH3
O
O
CH3
CH3
O
H
NH
O
H
NH2
H
S
H
N
O
H O
CH3
O
O
CH3
CH3
O
H
CH3
CH3
bacampicillin
ampicillin 1-
(ethoxycarbonyloxy)ethylester
pivampicillin
ampicillin pivaloyloxymethylester
•successful in acute
exacerbations of chronic
bronchitis
•hydrolyzed in vivo to ampicillin
•achieve significantly higher blood and tissue levels and attains peak blood levels
more rapidly than equimolar doses of oral ampicillin
•more frequently used in veterinary (horses) than in human medicine
•models for design of prodrugs of cephalosporins
Penicillins with broadened spectrum: ureidopenicillins
Compounds in which the amino group in α-position of the acyl is a part of urea moiety =
ureidopenicillins = „anti-pseudomonas“ penicillins
●their spectrum includes Pseudomonas aeruginosa
N
S
N
H
O
CH3
CH3
OH
O
O
N
H
N
O
O
N
O
CH3
HH
N
S
N
H
O
CH3
CH3
OH
O
O
N
H
N
O
N
O
HH
R
piperacillin
Tazocin ®
inj. plv. sol.(+ tazobactam)
R = H- azlocillin
R= CH3SO2- mezlocillin
•serious infections including otitis media, CNS infections …
Penicillins with broadened spectrum:
•compounds with the additional carboxyl in α-position of the acyl attached to amino
group in position 6
•in fact substituted malonic acids monoamides
N
S
O
N
H
CH3
CH3
OH
O
O
H
H
HO
OH
N
S
O
N
H
CH3
CH3
OH
O
O
H
H
HO
OH
S
carbenicillin ticarcillin
Timentin®
inj. sic. (+ clavulanic acid)
•infections of bones and junctures
(Staphylococcus aureus ),
gynecological & abdominal infections …
•ring analogy (benzene – thiophene)
Cephalosporins
• fungi Cephalosporium spp. (1948)
H
CH3
CH3
CH3
CH3
CH3
O
OH
OHOH
O
O
CH3
O
O
CH3
CH3
H
H
S
N
N
H
O
OH O
H
O
NH2
OH
O
H
O
CH3
O
N
S
O
OHO
CH3
CH3
HH
N
H
O
OH
ONH2
cephalosporin P1
cephalosporin C
cephalosporin N
… and other various structures
Cephalosporins
General structure
S
N
N
H
O
OH O
H
O
NH2
OH
O
H
O
CH3
O
N
SN
H
O
O
O
O
O
NH2
OH
CH3
O
NH2
OH O
S
N
N
H
R
3
OH O
R
8
O
H
O
R
7
1
2
3
45
6
7 8
cephalosporin C
•isolated from Cephalosporium spp.
cephamycin C
•isolated from Streptomyces lactadurans
S
N
N
H
R
3
OH O
R
8
O
H
O
R
7
S
N
N
H
R
3
OH O
R
8
O
H
O
R
7
Cephalosporins
Properties
●
electron pair on N5 is linked to conjugation with double bond ⇒ ↓ of electron density on N5 ⇒ ↓
of nucleophilicity of N5 ⇒ stability in acid media
●
also ↑ resistance to β-lactamases (cefalosporinases)
Cephalosporins
Compounds related to cephalosporin C, i.e. N-acylderivatives of 7aminocephalosporanic
acid.
S
N
N
H
O
OH O
H
O
NH2
OH
O
H
O
CH3
O
S
N
NH2
O
OH O
H H
O
CH3
O
S
N
NH2
O
OH O
H H
O
CH3
O
R Cl
O
S
N
N
H
O
OH O
H H
O
CH3
O
R
O
NOCl
or enzymes*
cephalosporin C 7-aminocefalosporanic acid
a semi-synthetic cephalosporin, or an
intermediate
*
glutarylacylase + D-amino acid oxidase
Cephalosporins
Compounds related to cephalosporin C, i.e. N-acylderivatives of 7aminocephalosporanic
acid
1st
generation: for parenteral administration only (not absorbed from GIT)
S S
N
OH
O CH3
O
O
HH
O
N
H
O
N
S
O
N
H
O O
N
+
OS
HH
cephalotin
Cefalotin®
Biotika inj. sic.
cefaloridin
Cephalosporins
Compounds related to cephalosporin C, i.e. N-acylderivatives of 7aminocephalosporanic
acid
2nd
generation: for oral administration
S
N
O
R
2
O
N
H
OH
H
O
NH2
R
1
R1
= -H, R2
= -CH3 cefalexin Cefaclen®
cps.
R1
= -OH, R2
= -CH3 cefadroxil Biodroxil®
tbl. obd.
R1
= -H, R2
=Cl cefaklor Ceclor®
cps.
Cephalosporins
Compounds related to cephalosporin C, i.e. N-acylderivatives of 7aminocephalosporanic
acid
2nd
generation: for parenteral use but with ↑ effect to G,
↑ resistance to β-lactamases
N
S
O
N
H
S
O
N
S
N
N
N
N
N
CH3
HH
OHO
N
S
O
N
H
O OH
N
+
O HH
S
O
O
O
NH2
O
cefazolin
Kefzol®
inj. sic.
cefsulodin
•Pseudomonas
Cephalosporins
Compounds related to cephalosporin C, i.e. N-acylderivatives of 7aminocephalosporanic
acid
2nd
generation: for both parenteral and p.o. administration, very resistant to β-
lactamase
N
S
O
N
H
OH O
S
O
OH
N
N
N
CH3
N
HH
O S
N
O
O NH2
O
O
HH
O
N
H
O
N
O
CH3
Rcefamandole
R = H- cefuroxime
Ceroxim®
tbl.
R = cefuroxime axetil
Zinnat®
tbl. obd.
CH3
CH
O
CH3
O
Cephalosporins
Compounds related to cephalosporin C, i.e. N-acylderivatives of 7aminocephalosporanic
acid
3rd
generation: for both parenteral and p.o. administration, very resistant to β-
lactamase
cefpodoxime proxetil
Orelox®
tbl. obd.
N
S
O
N
H
OOH
O
O
N
CH3
O
N
O
S
CH3
NH2
H
H
N
S
O
N
H
OO
O
O CH3
N
N
O
S
CH3
NH2
R
OCH3
O
O
CH3
CH3
cefotaxime
Claforan®
inj. sic.
R = H- cefpodoxime
R =
Cephalosporins
Compounds related to cephamycin C, i.e. N-acylderivatives of 7-methoxy-7aminocephalosporanic
acid
„New class = 4th
generation“ – for both parenteral and p.o administration –
resistant to β-lactamase
NH
O
N
S
O
CH3
O
OH O
O
S
NH2
O
H S
N
OOH
S
N N
N
N
O
O
CH3
NH
O
H
S
CH3
NH2
OH
O
cefoxitin
Mefoxin®
inj. sic.
cefminox
Cephalosporin analogues
N
H
O
N
O
O
CH3O
OH O
OH O
S N
N
OH
N
CH3
N
H
moxalactam
●
dihydrooxazine derivative related to 4th
generation of cephalosporins
●developed especially for treatment of meningitis (crosses the blood-brain barrier)
and anaerobic infections
Macrolides
•makrocyclic lactones with 10 – 40membered ring with 1 aminomonosaccharide and 1
„neutral“ monosacharide which can have an additional aminosaccharide attached
•1st
group (with larger ring)- natamycine, nystatine, amphothericine B – see antimycotics
•2nd
group – erythromycine group (erythromycine and its analogues, spiramycine, tylosine)
O
CH3
CH3
O
O
O
CH3
OH
R
4
O
O
O
N
CH3
CH3
CH3
CH3
O
CH3
CH3
OH
OH
CH3
CH3
R
1
CH3
z
R
2
R
3
desosamine
kladinose
R1
= -OH, -H
Z = 〉C=O, −CH2
N(CH3)-,〉C=N-O-CH3, 〉C=NOCH2OCH2CH2OCH3
R2
= -H, -F
R3
= -H, -CH3
R4
= -CH3 or R2
+ R4
= oxirane
Common structure of narrower group of erythromycine
(14 -15membered lakctone ring - erythromycine and analogues)
Macrolides
Site & mechanism of action
Macrolides
Site and mechanism of action
•Proteosynthesis inhibition
•act at 50S ribosome subunit
•inhibit the translocation of growing peptide from acceptor (A)
to peptide (P) site
•bacteriostatic effect
Spectrum:
•both G+
and GNeisseria,
Haemophillus, Brahmanella, Legionella …
Macrolides
Erythromycine and its analogues
O
CH3
CH3
OH
O
O
CH3
OH
CH3
O
O
O
N
CH3
O
CH3
CH3
CH3
O
CH3
CH3
OH
OH
CH3
CH3
OH
CH3
OCH3
CH3
OH
O
O
CH3
OH
CH3
O
O
O N
CH3
N
CH3
CH3
CH3
O
CH3
CH3
CH3
OH
CH3
CH3
OH
CH3
OH
erythromycine
•isolated 1952 from Streptomyces
erythreus
•poor biological availability ⇒ lipophilic
salts (stearate, ethylsuccinate …)
•external form (lotions …) – treatment
of acne vulgaris
Porphyrocin®
tbl.
azithromycine
●semi-synthetic compound
Sumamed®
tbl. obd.
Macrolides
Synthesis of azithromycine from erythromycine
CH3
OH
CH3
O
CH3
OH
CH3
OH
CH3
OH
CH3
N
CH3
OH
CH3
OH
OH
CH3 S
O
O
Cl
CH3
OH
CH3
N
CH3
OH
CH3
OH
O S
O
O
CH3
CH3
OH
CH3
OH
N
H
CH3
OH
CH3
O S
O
O
CH3
CH3
OH
CH3
OH
N C
+
CH3
OH
CH3
CH3 S
O
O
O
CH3
OH
CH3
OH
N
CH3
OH
CH3
O
+
H
H
CH3
OH
CH3
OH
N
CH3
OH
CH3
OH
CH3 S
O
O
Cl O
CH3
NCH3
OH
OH
OH
CH3
CH3
OH
CH3
OH
N
H
CH3
OH
CH3
CH3
OH
CH3
OH
N
CH3
OH
CH3
CH3
NH2OH
-
H2O
- H+
- H2O NaBH4
HCOH
HCOOH
Macrolides
Erythromycine and its analogues
O
O
CH3
CH3
CH3
O
O
CH3
CH3
OH
O
O
O
O
N
CH3
CH3
CH3 CH3OH
O
CH3
CH3
CH3
OH
OH
CH3
CH3
O
CH3
CH3
O
O
O
O
CH3
OH
O
O
CH3
CH3
OH
CH3
OH
CH3
CH3
OH
CH3
N
CH3
N
OH
CH3 CH3
CH3
O O
O
CH3
6-O-methylerythromycine
clarithromycine
•also some strains of Mycobacterium avium
Klacid®
tbl. obd.
roxithromycine
Rulid®
tbl.
Macrolides
Erythromycine and its
analogues
O
OH
O
CH3
H
O
O
O
CH3
CH3
CH3
CH3
CH3
CH3
F
OH
OHOH
CH3
O
O
H
OH
CH3
N
CH3
CH3
O
CH3
CH3
O
NOH CH3
CH3
CH3
O
O
O
OH
CH3
CH3
CH3
O
O
N
H
O
O
OH
OH
CH3
CH3
CH3
CH3
CH3
CH3
O
O
CH3
CH3
H
H
H
H
8-fluoroerythromycine
flurithromycine dirithromycin
Macrolides
Erythromycine and its analogues
O
O
CH3
CH3
O
OH
CH3
CH3
O
O
OCH3
CH3
OH
O
O
N
CH3
CH3 CH3
O
CH3
OH
CH3
O
CH3
CH3
O
O
O
O
CH3
OH
O
O
CH3
CH3
OH
CH3
OH
CH3
CH3
OH
CH3
N
CH3
N
OH
CH3
CH3
CH3
O
CH3
oleandomycine
•isolated 1954 from Streptomyces
antibioticus
lexithromycine
L-oleandrose
O
N
N
O
O
O
N
O
N
O O
O
N
OHCH3
O
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
telithromycine
Ketek® tbl.
„More free“ erythromycine analogues: Ketolides
•2 keto-moieties on lactone ring (+ 1 ester carbonyl
+ 1 cabamate carbonyl)
•good biological availability
Macrolides
Compounds with 16membered lactone ring unsaturated in positions 10 and 12
O
H
CH3
N
CH3
CH3
OCH3
O
O
O
CH3
O
O
OH N
CH3
CH3
CH3
O
O
H
OH
CH3
OHCH3
CH3 O
O
H
R
O
O
O
CH3
O
CH3 O
OHO
O
CH3 O
OH
N
CH3
O
CH3
CH3CH3
O
CH3
OH
CH3
O
O
CH3
CH3
spiramycine (syn. rovamycin)
•isolated 1954 from Streptomyces ambofaciens
R = HCO- spiramycine A = spiramycine I
CH3CO- spiramycine B = spiramycine II
CH3CH2CO- spiramycine C = spiramycine III
Rovamycine®
tbl. obd.
josamycin
•also Mycoplasma
Wilprafen®
tbl. obd., Alpucine®
premix a.u.v.
O
CH3
O
O
CH3
O
CH3
O
CH3
O
O
O
CH3
NOH CH3
CH3
O
O
OHCH3
O
CH3
CH3
OH
O
O
O
O
CH3
O
CH3 O
OHO
O
O
O
N
CH3
CH3
O
CH3
CH3
CH3
CH3
O
O
O
CH3
CH3
O
CH3
O
O
CH3
Macrolides
Compounds with 16membered lactone ring unsaturated in positions 11 and 13
rokitamycin
miokamycin
(Poly)peptide antibiotics
•site of action: cytoplasmic membrane
•mode of action: ionophores: cause uncontrolled
exchange of ions between inside and outside media of a
bacterial cell and thus ionic imbalance and cell death
•very toxic, external application
•totally known approx. 200 ATB of polypeptid structure
•homomeric peptides: contain amino acids only (often D-)
•heteromeric peptides: except amino acids also other
carboxylic acids
•if they are cyclic, then homodets and heterodets
Tyrothricin
•mixture from Brevibacillus brevis
H
N
O
H
NH O
H CH3
CH3
NH
O
H
NH2
NH
O
H
NH
OH
OH
NHH
OH O
O
NH
HNH2
O
O
H
NH
O
H
NH
O
CH3
CH3
N
H
N
H
NH
OO
NH
N
HO
CH3
CH3
CH3
CH3
ON
H
N
H
O
CH3
CH3
O
N
H
NH
N
HO
CH3
CH3
CH3
CH3
ON
H
CH3
N
H
O
O
N
H
NH
N
HO
CH3
CH3
O
CH3
CH3
N
H
CH3
N
H
O
O
N
H
N
H
OH
O
N
H
CH3
CH3
O
H
H
H
H
H
H
H
H
H
H
H
H
H
H
tyrocidin A
tyrocidins A – E total 80%
decapeptides
gramicidin A1
20 % of gramicidines A1, A2, C1 and C2
pentadecapeptides
Polymyxins and colistins
N
O
N
ON
N
O
N
O H
N
O
N
N
O
N
N
O
O
N
O
N
N
O
N
O
N
N
O
O
H
HH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H H
CH3
D-Phe
polymyxin B
colistin A: D-Leu instead D-Phe
Bacitracin
N
S
NH2
CH3
Leu
O
CH3
Glu
IleLys
Asn
O
Asp
NH
His
Ile
Phe
NH2
L-Cys
L-Ile
bacitracin A
Framykoin®
ung., Pamycon®
plv. (+ neomycin B)
Aminoglycosides
➔ aminosaccharide glycosides produced by strains of Streptomyces genus
• Streptomycin group
• Neomycin group
• Kanamycin and gentamycin group
Mechanism of action
• protheosynthesis inhibition
• they avoid accurate reading of the genetic code and binding of peptidyltRNA
to the peptide binding site
• effect bacteriostatic – bactericidal
Spectrum
G+
< GBacillus
anthracis, Bordetella pertussis, Brucella, Corynebacterium diphteriae,
E. coli, Enterobacter, Haemophillus, Mycobacterium tuberculosis…
Aminoglycosides
1. Streptomycin group
O
O
O
OH
O
NH
N
H
OH
OH
CH3
OH
OH
OH
OH
N
H
NH2
NH
NH2
NH
CH3
R
R = -CHO streptomycin
•isolated 1944 from Streptomyces fradiae
•used to M. tuberculosis in combination with other tuberculostatics
•bactericidal
Streptomycin „Grünenthal“®
inj. sic., Streptowerfft®
a.u.v
R = -CH2OH dihydrostreptomycin
Depomycine®
a.u.v. inj. (+ benzylpenicillin)
streptidine = aglycone
N-methyl-L-glucosamine
furanose (streptose or
dihydrostreptose)
Aminoglycosides
2. Neomycin group
O
OH
OHO
NH2
NH2
H
O
OH
OH
O
NH2
OH
NH2NH2
H
O O
H
OH
R
OH
R= -NH2 neomycin B
•mixture of neomycins isolated from
Streptomyces fradiae in 1949
Framykoin®
ung., Pamycon®
plv. (+ bacitracin)
R = -OH paromomycin
•not absorbed from GIT
•used for Entamoeba histolytica
Humatin®
cps.
deoxystreptamine = aglycon
Aminoglycosides
3. Group of kanamycin and gemtamycin
Kanamycin subgroup
O NH
OH
O
O
NH2
OH
O
NH2
OH
OH
OH
OH
OH
NH2
R
O
OH
NH2
O
OH
NH2
O
O
NH2
OH
O
NH2
NH2
OH
OH
OH
NH2
H
H
R = -H kanamycin
Kanacol® a.u.v. inj.
R= amikacin
Amikin® inj.
tobramycin
Tobi Nebuliser Solution®
inh. sol.
•treatment of chronic
pulmonary infection caused
by Pseudimonas in patients
with cystic fibrosis
Aminoglycosides
3. Group of kanamycin a gemtamycin
Subgroup of gentamycin
O
OH
OH
OH
NH2
O
NH2
NH2
H
OO
O
NH2
OH
N
H
H
OH
N
H
CH3
OH
CH3
R
2
R
1
O
NH2
NH2
H
R2
=
gentamycin
Garasone® gtt. opht.
(+betamethason)
Diagen® a.u.v.
sisomycin
R1
= H- H- CH3CH2-
netilmycin
Netromycine® inj.
•serious infections,
sepsis …