1. Aminoglycosides: BactericidalAminoglycosides: Bactericidal
Inhibitors of Protein SynthesisInhibitors of Protein Synthesis

2. Aminoglycosides
 Most commonly employed agents
 Gentamicin, tobramycin, amikacin
 Narrow-spectrum antibiotics
 Bactericidal
 Use – aerobic gram-negative bacilli
 Can cause serious injury to inner ear and
kidney
 Not absorbed from the GI tract
 Microbial resistance

3. Fig. 86-1. Structural formulas of the major aminoglycosides.

4. Fig. 86-2. Mechanism of action of aminoglycosides.
A, Protein synthesis begins with binding of the 50S and 30S ribosomal subunits to messenger RNA (mRNA), followed by attachment of
the first amino acid of the new protein to the 50S subunit. As the ribosome moves down the mRNA strand, additional amino acids are
added to the growing peptide chain. When the new protein is complete, it separates from the ribosome and the ribosomal subunits
separate from the mRNA. B, Aminoglycosides bind to the 30S ribosomal subunit and can thereby (1) block initiation, (2) terminate
synthesis before the new protein is complete, and (3) cause misreading of the genetic code, which causes synthesis of faulty proteins.

5. Bacterial resistance
Bacterial resistance to aminoglycosides occurs via
one of three mechanisms that prevent the normal
binding of the antibiotic to its ribosomal target:
(1)Efflux pumps prevent accumulation of the
aminoglycoside in the cytosol of the bacterium.
(2) Modification of the aminoglycoside prevents
binding to the ribosome.
(3)Mutations within the ribosome prevent
aminoglycoside binding.

6. Gentamicin (Garamycin)Gentamicin (Garamycin)
 Used to treat serious infections caused by
aerobic gram-negative bacilli
 Pseudomonas aeruginosa
 Escherichia coli
 Klebsiella
 Serratia
 Proteus mirabilis
 Adverse effects
 Nephrotoxicity
 Ototoxicity

7. Other AminoglycosidesOther Aminoglycosides
 Tobramycin (Nebcin)Tobramycin (Nebcin)
 Amikacin (Amikin)Amikacin (Amikin)
 NeomycinNeomycin
 Kanamycin (Kantrex)Kanamycin (Kantrex)
 StreptomycinStreptomycin
 Paromomycin (Humatin)Paromomycin (Humatin)

8. Quinolones

9. Introduction
 The quinolones have a number of advantages over
other classes of antibacterial agents.
 They are effective against many organisms, well-
absorbed orally, well-distributed in tissues, and they
have relatively long serum half-lives and minimal
toxicity.
 Because of deep-tissue and cell penetration, they
are useful for urinary tract infections, prostatitis,
infections of the skin and bones, and penicillin-
resistant sexually transmitted diseases.

10. The quinolone antimicrobials comprise a group of
synthetic substance possessing in common an N-alkylated-
3-carboxypyrid-4-one ring. The discovery of quinolone is
an epoch-making events. Since 1962 the first quinolone,
Nalidixic acid was developed, more than 100,000
quinolone compounds have been synthesized and screened
their pharmacological activities. Currently, there are more
than 20 quinolones used in clinic. The advantages of this
kind of drugs are their lower cost in synthesis together with
the excellent activities.
X N
O
COOH
R1
R2
R

11. Brief History and Overview
 The history can be traced to
the discovery of an
antibacterial by-product
formed during the synthesis
of antimalarial agent
Chloroquine, an isomer of
key intermediate, 7-chloro-
1-ethyl-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid (1).
NCl
HN
N
Chloroquine
N
O
COOH
Cl
1

12. Brief History and Overview
 In 1962, Lesher et al. described
the 1-ethyl-7-methyl-4-oxo-1,4-
dihydro-1,8-naphthyridine-3-
carboxylic acid (2), also known
as Nalidixic acid. It was the first
commercially available
compound of this class and was
approved for treatment of
urinary tract infections in 1964.
N N
O
COOH
H3C
2
Nalidixic acid
N
O
COOH
Cl
1

13. The first-generation
quinolones

14.  Norfloxacin, a fluoroquinolone with a broad
spectrum of antibacterial activity, was patented in
1978 .
 Between 1978 and 1982, many new
fluoroquinolones were prepared and patented.
These fluoroquinolones now classified as second-
generation quinolones.
N
O
OH
O
N
HN
F

15. The second-generation quinolones

16. The third-generation quinolones
 A third advance was made in early 1990s. All third-
generation fluoroquinolones have significantly
improved activity against gram-positive bacteria,
notably streptococcus pneumoniae. Some of them
have good activity against anaerobes and atypical
pathogens.

17. *withdrawn from the market in 1999
Generation Drug Names Spectrum
1st
nalidixic acid
cinoxacin
Gram- but not
Pseudomonas species
2nd
norfloxacin
ciprofloxacin
enoxacin
ofloxacin
Gram- (including
Pseudomonas species),
some Gram+ (S. aureus)
and some atypicals
3rd
levofloxacin
sparfloxacin
moxifloxacin
gemifloxacin
Same as 2nd
generation
with extended Gram+ and
atypical coverage
4th
*trovafloxacin
(withdrawn from the
market in 1999)
Same as 3rd
generation
with broad anaerobic
coverage

18. Mechanism of action
Quinolones enter the cell by passive
diffuse. Intracellularly, they inhibit the
synthesis of bacterial DNA by
interfering with the action of DNA
gyrase ， topoisomerase .Ⅳ

19. The chromosome of bacteria is composed of helical double-stranded DNA
and contains 60 to 70 spatial regions of organisation, termed domains of
supercoiling. Each domain is attached to an RNA core and is organised by
supercoiling which occurs quite independently of the DNA coiling in any
other domain.
Supercoiling is controlled by the enzyme DNA gyrase, which introduces
transient breaks into both DNA strands of each domain, removes about
400 turns from its DNA helix, then reseals the DNA so locking in the
supercoiling.
This supercoiled state is essential to the well-being of bacteria as it
enables them to accommodate their chromosome within the confines of
their cell envelope.
The target site of action of the quinolone antibacterial agents is DNA
gyrase and its inhibition by them sets off a complex series of events which
ultimately causes bacteria to die.

20. Mechanism of action
Model of the formation of negative DNA supercoils
by DNA gyrase.
(1) A node of positive is created for(+) superhelix.
(2) The enzyme introduces a double-strand break in the DNA and
passes the front segment through the break.
(3)The break is then resealed, creating a negative (-) supercoil.
Quinolones inhibit both the nicking and closing activity of the
gyrase.

21. Mechanism of action
A A
B
B
• •
Binding sites of quinolones
ATP-
ATP-

22. Gram-positive
bacteria
Some Staphylococcus aureus,
Streptococcus pyogenes, Virdans
group streptococci, Streptococcus
pneumoniae
Gram-negative
bacteria
Neisseria spp. Haemophilus
influenzae
Many Enterobacteriaceae, Some
Pseudomonas aeruginosa
Anaerobic bacteria Some clostridia spp, Some
Bacteroides spp.
Atypical bacteria Chlamydia and Chlamydophilia,
Mycoplasma pneumoniae,
Legionella spp
Mycobacteria Mycobacterium tuberculosis,
Mycobacterium avium complex,
Mycobacterium leprae
Antimicrobial Activity of the Quinolones (oral)

23. Resistance Mechanisms
 Mutations that enhance antibiotic efflux capability
 Bacterial chromosomal mutations for genes that
encode for bacterial DNA gyrase and Topo IV
 Mutations in outer membrane porins (Gram-)

24. MECHANISMS OF RESISTANCE TO QUINOLONESMECHANISMS OF RESISTANCE TO QUINOLONES
• Changes in the protein targets.
• DNA gyrase
• Topoisomerase IV.
• Reduction in the accumulation of the quinolone.
- Decrease in permeability.
- Increase in active efflux system(s).
• DNA gyrase and topoisomerase IV protection - qnr gene