Download 15-2-3to6大环内酯氨基苷四环素人工合成抗菌药

Section 15. Infection disease
and Anti-infective drugs
(第十五篇 感染性疾病与抗感染药)
第二部分
content
Part 3. Macrolides(大环内酯类),
Lincomycin(林可霉素类), and
Vancomycin(万古霉素)
Part 4. Aminoglycosides(氨基糖苷类) and
Polymyxins(多黏菌素类)
Part 5. Tetracyclines(四环素类) and
Chloramphenicol(氯霉素)
Part 6. Synthetic antimicrobial agents(人工
合成抗菌药)
细菌蛋白质的合成的简介

3
细菌蛋白质的
合成的简介
30S
30S
1
3
2
1
21
aa1-tRNA
3
1
P
2
3T
1
3
2
1
1
R
3
2
1 A
50S
3
2
T
mRNA
mRNA
31
3TmRNA
2T
TmRNA
aa
aa32-tRNA
-tRNA
A
P
50S
Part 3
Macrolides(大环内酯类),
Lincomycin(林可霉素类), and
Vancomycin(万古霉素)
Macrolides
History
1952
Erythromycin(红霉素)
1970s Acetylspiramycin(乙酰螺旋霉素)
Medecamycin(麦迪霉素)
josamycin(交沙霉素)
1980s Clarithromycin (克拉霉素)
Roxithromycin(罗红霉素)
Azithromycin(阿奇霉素)
Macrolides

14碳环大环内酯类：
16碳环大环内酯类：

红霉素(erythromycin)


克拉霉素
(clarithromycin)




罗红霉素
(roxithromycin)
15碳环大环内酯类：

阿奇霉素
(azithromycin)


吉他霉素(kitasamycin)
交沙霉素(josamycin)
乙酰螺旋霉素
(acetylspiramycin)
麦迪霉素(medecamycin)
Macrolides
STRUCTURE:
(克拉霉素)
(红霉素)
(阿奇霉素)
First generation
Macrolides
Erythromycin (红霉素)

Antimicrobial activity



Gram-positive organisms: pneumococci（肺炎双球菌 ）,
streptococci（链球菌）, staphylococci（葡萄球菌） ,
diphtheriae （白喉）etc
Gram-negative organisms:legionella（军团菌）,bacillus
pertussis(百日咳), brucella(布氏) ,
meningococci（脑膜炎球菌）, diplococcus gonorrhoeae （淋
病双球菌） etc
Others: mycoplasma(支原体), chlamydia trachomatis(沙眼衣
原体), rickettsia(立克次体), spirotchete (螺旋体 ),
anaerobes(厌氧菌) etc.
Mechanism of action


Macrolides
Target
50s ribosomal RNA
Mechanism
inhibition of translocation of mRNA
Macrolides
① Chloramphenicol
② Clindamycin
Macrolides
③ Tertracyclines
Macrolides
Pharmokinetics



Not stable at acid pH
Metabolized in liver
Excreted in bile
Drugs:



erythromycin stearate(硬脂酸红霉素）
erythromycin ethylsuccinate（琥乙红霉素，利
君沙）
erythromycin estolate（无味红霉素）
Macrolides
Clinical uses




As penicillin substitute in penicillinallergic or resistant patients with
infections caused by staphylococci,
streptococci and pneumococci
Pertussis，diphtheriae
Legionella and mycoplasma pneumonia
H.p infection
Macrolides
Mechanism of resistance



Modification of the ribosomal binding
site
Production of esterase that hydrolize
macrolides
Active efflux system
Macrolides
Adverse reactions



Gastrointestinal effects
Liver toxicity
Cardiotoxicity
Macrolides
Second generation

Advantage :






Broader spectrum, higher activity
Orally effective
High blood concentration
Longer t 1/2
Less toxicity
Mainly used in respitory tract
infection
Macrolides
Azithromycin (阿齐霉素,丽珠奇乐）





Has the strongest activity against
mycoplasma pneumoniae（肺炎支原体）
More effective on Gram-negative
bacteria
Well tolerated
T1/2 :35~48h
once daily
Mainly used in respitory tract infection
Macrolides
Roxithromycin （罗红霉素，严迪）





1987
France
The highest blood concentration
F
72%~85%
Respiratory tract infection and soft
tissue infection
Low adverse effects
Macrolides
Clarithromycin（甲红霉素,克拉霉素）



Has the strongest activity on Grampositive bacteria, legionella pneumophila,
chlamydia pneumoniae and H.p
Good pharmacokinetic property
Low toxicity
Macrolides
Third generation



Ketolides(酮基大环内酯类)
Ketolides are semisynthetic 14-membered-ring
macrolides, differing from erythromycin by
substitution of a 3-keto group for the neutral sugar Lcladinose.
Telithromycin (泰利霉素)


It is active in vitro against Streptococcus pyogenes, S
pneumoniae, S aureus, H influenzae, Moraxella catarrhalis,
mycoplasmas, Legionella, Chlamydia, H pylori, N gonorrhoeae, B
fragilis, T gondii, and nontuberculosis mycobacteria.
Many macrolide-resistant strains (macrolides-lincomycinsstreptogramins, MLS)are susceptible to ketolides because the
structural modification of these compounds renders them
poor substrates for efflux pump-mediated resistance and
they bind to ribosomes of some bacterial species with higher
affinity than macrolides.
Lincomycin & Clindamycin
Part 3-2 Lincomycin (林可霉素)and
Clindamycin（克林霉素）
① Chloramphenicol
② Clindamycin
Macrolides
③ Tertracyclines
Mechanism : Binding to 50s ribosome subunit and inhibiting
protein synthesis
Lincomycin & Clindamycin


Antimicrobial activity
 Gram-positive organisms
 Bacteroide fragilis and other
anaerobes
Pharmacokinetics
 Absorbed well
 Penetrate well into most tissues
including bone
Lincomycin & Clindamycin

Clinical uses



Severe anaerobic infection
Acute or chronical suppurative osteomylitis（化脓性骨
髓炎）, arthritis caused by susceptive organisms
especially Staphylococci aureus（金黄色葡萄球菌）
Adverse reactions


Gastrointestinal effects: severe diarrhea and
pseudomembranous enterocolitis caused by Clostridium
difficile（难辨梭状芽孢杆菌）:
 vancomycin & metronidazole(甲硝唑)
Impaired liver function , neutropenia(中性粒细胞减少)
Vancomycin
Part 3-3 ----------last choice
Vancomycin (万古霉素)
& Teicoplanin（替考拉宁）
Vancomycin
Vancomycin (万古霉素)

Mechanism of action--Inhibit cell wall synthesis
-Lactam antibiotics
vancomycin
transpeptidase
Vancomycin
Vancomycin(万古霉素)

Antimicrobial spectrum:


Narrow spectrum, active only against grampositive bacteria paticularly staphylococci
Pharmacokinetics


Poorly absorbed from intestinal tract, iv
Excreted from glomerular filtration 90%
Vancomycin
Vancomycin(万古霉素)

Clinical uses



Infection caused by MRSA, MRSE and
penicillin-resistant pneumococcus
Treatment of antibiotic-associated
enterocolitis caused by clostridium
difficile po
Adverse reaction


Ototoxicity & nephrotoxicity
Red-man syndrome
Vancomycin
Teicoplanin(替考拉宁)



Similar to vancomycin in mechanism and
antimicrobial spectrum
Can be given im as well as iv
Less adverse reactions
Linezolid
Part 3-4 Oxazolidinones(恶唑烷酮类)
Linezolid (利奈唑胺)


Linezolid is a member of the oxazolidinones, a new class of
synthetic antimicrobials.
Antimicrobial spectrum:




Mechanism of action


It is active against gram-positive organisms including staphylococci,
streptococci, enterococci, gram-positive anaerobic cocci, and grampositive rods such as corynebacteria and Listeria monocytogenes.
It is primarily a bacteriostatic agent except for streptococci for
which it is bactericidal.
There is modest in vitro activity against Mycobacterium
tuberculosis.
Linezolid inhibits protein synthesis by preventing formation of the
ribosome complex that initiates protein synthesis. Its unique
binding site, located on 23S ribosomal RNA of the 50S subunit,
results in no cross-resistance with other drug classes.
Mechanism of Resistance

Resistance is caused by mutation of the linezolid binding site on
23S ribosomal RNA.

Adverse reaction






The principal toxicity of linezolid is hematologic—reversible and
generally mild.
Thrombocytopenia(血小板减少症) is the most common manifestation
(seen in approximately 3% of treatment courses), particularly when
the drug is administered for longer than 2 weeks.
Neutropenia may also occur, most commonly in patients with a
predisposition to or underlying bone marrow suppression.
Pharmacokinetics

Linezolid is 100% bioavailable after oral administration and has a
half-life of 4–6 hours. It is metabolized by oxidative metabolism,
yielding two inactive metabolites.
It is neither an inducer nor an inhibitor of cytochrome P450
enzymes. Peak serum concentrations average 18 g/mL following a
600 mg oral dose. The recommended dose for most indications is
600 mg twice daily, either orally or intraveneously.
Clinical uses




Linezolid
vancomycin-resistant E faecium infections;
nosocomial pneumonia(医院获得性肺炎);
community-acquired pneumonia(社区获得性肺炎);
skin infections
Streptogramins
Part3-5 Streptogramins (链阳性菌素)


Streptogramins are effective in the treatment of
Vancomycin-resistant Staphylococcus aureus (VRSA)
and Vancomycin-resistant enterococcus (VRE), two of
the most rapidly-growing strains of multidrugresistant bacteria.
Members include:




Quinupristin/dalfopristin (喹奴普丁－达福普丁 )
Pristinamycin
Virginiamycin
NXL 103, a new oral streptogramin currently in phase II
trials (As of). It will be used to treat respiratory tract
infections.
Daptomycin
Part3-6 lipopeptide antibiotic

Daptomycin(达托霉素)
Mechanism of action

Disruption of the bacterial membrane
through the formation of transmembrane
channels, resulting in a loss of membrane
potential leading to inhibition of protein, DNA
and RNA synthesis, which results in bacterial
cell death.
Antimicrobial spectrum:


Daptomycin
Daptomycin is unable to permeate the outer
membrane of Gram-negative bacteria, thus its
spectrum is limited to Gram-positive
organisms only.
Daptomycin has activity against Staphylococci
(including MRSA, VISA, and VRSA),
Enterococci (both E. faecalis and E.faecium,
including VRE), and Streptococci (including
DRSP), as well as most other aerobic and
anaerobic Gram-positive bacteria.
Polypeptide antibiotics



Vancomycin & Teicoplanin
Polymyxins
bactitracin
Polymycins




Active only against gram-negative rods,
particularly P.aeruginosa
Mechanism:increase permeability of cell
membrane
Mainly used in P.aeruginosa infection
when other drugs are resistant
Toxicity: nephrotoxicity & neurotoxicity
Baciteracin




Active against gram-positive bacteria
Inhibit cell wall formation
No cross-resistance with other agents
Topical use only because of
nephrotoxicity
Part 4
Aminoglycosides(氨基糖
苷类) & Polymyxins(多黏
菌素类)
Aminoglycosides （氨基苷类）
Summarization of aminoglycosides
The aminoglycosides are compounds contanining
characteristic amino sugars joined to a hexose
nucleus in glycosidic(糖苷） linkage. Most aminoglycosides, which are prepared by natural
fermentation from various species of streptomyces,
are a group of bactericidal drugs sharing chemical,
antimicrobial, pharmacological, and toxic
characteristics.
Aminoglycosides （氨基苷类）

Natural Aminoglycosides

链霉素(streptomycin)

新霉素(neomycin)

妥布霉素(tobramycin)

卡那霉素(kanamycin)

大观霉素(spectinomycin)


Semisynthetic Aminoglycosides
阿米卡星
(amikacin)
庆大霉素(gentamicin)
西索米星(sisomicin)
小诺米星(micronomicin)
奈替米星(netilmicin)
Structure of streptomycin
Structures of several important
aminoglycoside antibiotics.
Aminoglycosides


Spectrum of activity
Aminoglycosides are effective against
aerobic gram-negative bacteria, especially
in bacteremia, sepsis, or endocarditis.
Aminoglycosides
Mechanism of action
The mechanism of Aminoglycosides is to inhibit
protein synthesis in susceptible microorganisms by
interfering with the initiation complex of peptide
formation.

inducing misreading of the code on the mRNA
template, which causes incorporation of
inappropriate amino acid into peptide.

by rupturing the polysomes into monosome,
which become nonfunctional.

Inhibiting protein synthesis
氨基苷类
氨基苷类
氨基苷类
大环内酯类
四环素类
氯霉素类
林可霉素类
Mechanisms of resistance
Three principal mechanisms have been established:
(1) production of a transferase enzyme or enzymes inactivates the
aminoglycoside by adenylylation, acetylation, or phosphorylation.
This is the principal type of resistance encountered clinically.
(Specific transferase enzymes are discussed below.)
(2) There is impaired entry of aminoglycoside into the cell. This
may be genotypic, ie, resulting from mutation or deletion of a
porin protein or proteins involved in transport and maintenance
of the electrochemical gradient; or phenotypic, eg, resulting
from growth conditions under which the oxygen-dependent
transport process described above is not functional.
(3) The receptor protein on the 30S ribosomal subunit may be
deleted or altered as a result of a mutation.
Aminoglycosides
Pharmacokinetics
•
poorly absorbed from the gastrointestinal tract.
•
must be given intramuscularly or intravemously for
systemic infection.
• excreted almost entirely unchanged by glomerular
filtration, which is greatly reduced in renal impairment,
causing toxic blood levels.
Aminoglycosides
Adverse effects
• Ototoxicity
Aminoglycosides are potentially toxic to branches
of the eighth cromial nerve. The
evidence
indicates that the sensory receptor portions of the
inner ear ( hair cells of the cochlea) are affected
rather than the nerve itself.
cochlear damage(耳蜗损伤):
Kanamycin>Amikacin> sisomicin>gentamicin>tobramycin
vestibular impairment(前庭受损):
Kanamycin>Streptomycin>sisomicin> gentamicin> tobramycin
Aminoglycosides
Nephrotoxicity
• Nephrotoxicity may develop during or after use of
an aminoglycosides, those elderly,
debilitated patients, and patients with preexisting
renal dysfunction.
• Nephrotoxicity is dose dependent and damage to
the proximal tubular epithelium usually begins
after five to seven days of therapy.
• The toxicity results from accumulation and retention
of aminoglycosides in the proximal tubular cells.
• The renal injury may lead to acute renal failure.
Neomycin>Kanamycin>gentamicin>Streptomycin or
tobramycin>Amikacin
Aminoglycosides
Neuromuscular blockade
The aminoglycosides rarely cause neuromuscular
blockade that can lead to progressive flaccid
paralysis and potentially total respiratory
arrest.
The risk is greatest after rapid iv
administration.
Neomycin>Streptomycin >Amikacin or
Kanamycin>gentamicin > tobramycin
Clinical uses


Aminoglycosides are mostly used against gramnegative enteric bacteria, especially when the isolate
may be drug-resistant and when there is suspicion of
sepsis.
They are almost always used in combination with a lactam antibiotic to extend coverage to include
potential gram-positive pathogens and to take
advantage of the synergism between these two
classes of drugs.

Penicillin-aminoglycoside combinations also are used to
achieve bactericidal activity in treatment of enterococcal
endocarditis and to shorten duration of therapy for viridans
streptococcal and staphylococcal endocarditis. Which
aminoglycoside and what dose should be used depend on the
infection being treated and the susceptibility of the isolate.
Aminoglycosides
Streptomycin （链霉素）
Spectrum of activity and therapy of Streptomycin
(1) most gram-negative bacilli and some gram-positive
cocci.
(2) organisms that cause plague(鼠疫） and in
combination with penicillin G against bacterial
endocarditis.
(3) antituberculosis agent.
A major disadvantage of streptomycin therapy is the
development of frequent bacterial resistance to the
drug.
Aminoglycosides
Untoward effects of streptomycin
 Hypersensitivity reactions can occur.
 Labyrinthine damage (迷路破坏) and vestibular
disturbances can occur. Streptomycin should not be
given with other ototoxic drugs .
 Renal effects are minimal at normal doses.
 Neuromuscular junction blockade may occur when
streptomycin is given at high doses and in combination
with curariform drugs (箭毒样药物).
Aminoglycosides
Gentamicin
used in the treatment of a serious infections caused
by a large number of gram-negative organisms.
Gentamicin is of the first choice when these infections
occurs
1) urinary tract infections, bacteremia resulting
from Escherichia coli.
2) bile duct and urinary tract infections caused by
proteus mirabilis.
Gentamicin
Gentamicin
It is effective against both gram-positive and gram-negative
organisms, and many of its properties resemble those of other
aminoglycosides.
It is active alone, but also as a synergistic companion with –lactam
antibiotics, against pseudomonas, proteus, enterobacter, klebsiella,
serratia, stenotrophomonas, and other gram-negative rods that
may be resistant to multiple other antibiotics.
Like all aminoglycosides, it has no activity against anaerobes.
Clinical uses
Gentamicin
Intramuscular or intravenous administration
 used in the treatment of a serious infections caused by a
large number of gram-negative organisms.
 Gentamicin is of the first choice when these infections
occurs
1) urinary tract infections, bacteremia resulting from
Escherichia coli.
2) bile duct and urinary tract infections caused by
proteus mirabilis.
3) Gentamicin combined with carbenicillin is of the first
choice for the treatment of infected burns, bacteremia,
urinary tract infection resulting from pseudomonas
aeruginosa.
Gentamicin
Topical administration



Creams, ointments, and solutions containing
0.1–0.3% gentamicin sulfate
Clinical use: infected burns, wounds, or skin
lesions and the prevention of intravenous
catheter infections. 10 mg can be injected
subconjunctivally for treatment of ocular
infections.
Topical gentamicin is partly inactivated by
purulent exudates.
Gentamicin
Intrathecal administration



Meningitis caused by gram-negative bacteria has been
treated by the intrathecal injection of gentamicin
sulfate, 1–10 mg/d.
Neither intrathecal nor intraventricular gentamicin
was beneficial in neonates with meningitis, and
intraventricular gentamicin was toxic, raising
questions about the usefulness of this form of
therapy.
the availability of third-generation cephalosporins for
gram-negative meningitis has rendered this therapy
obsolete in most cases.
Gentamicin
Adverse effects of gentamicin
 Ototoxicity (耳毒性) is the most serious
effect.(The incidence of ototoxicity is in part
genetically determined, having been linked to point
mutations in mitochondrial DNA, and occurs in 1–5%
for patients receiving gentamicin for more than 5
days. )
 Nephrotoxicity can occur.
 Hypersensitivity can also occur.
Aminoglycosides
Tobramycin 妥布霉素
Spectrum of activity of Tobramycin
Tobramycin has a spectrum of activity similar
to that of gentamicin but may be slightly more
effective against pseudomonas（假单胞菌属）.
Pharmacokinetic properties of tobramycin
virtually identical with those of gentamicin.
Adverse effects of Tobramycin
Ototoxicity
Tobramyci
n
Tobramycin vs Gentamicin
Spectrum of activity of Tobramycin
 Tobramycin has almost the same antibacterial spectrum as
gentamicin with a few exceptions.
 Gentamicin is slightly more active against serratia(沙雷氏菌),
whereas tobramycin is slightly more active against pseudomonas
（假单胞菌属）;
 Enterococcus faecalis (粪肠球菌)is susceptible to both
gentamicin and tobramycin, but E faecium （屎肠球菌）is
resistant to tobramycin.
Adverse effects of Tobramycin
 Ototoxicity
 Nephrotoxic
 Nephrotoxicity of tobramycin may be slightly less than that
of gentamicin, but the difference is clinically inconsequential.
Tobramycin more active than gentamicin versus pseudomonas;
Tobramycin may also have less nephrotoxicity
Tobramyci
n
Clinical uses


Gentamicin and tobramycin are otherwise
interchangeable clinically.
Tobramycin is also formulated in solution (300 mg in 5
mL) for inhalation for treatment of Pseudomonas
aeruginosa lower respiratory tract infections
complicating cystic fibrosis.
Neomycin & Kanamycin
Neomycin & Kanamycin

Antimicrobial Activity & Resistance





gram-positive and gram-negative bacteria and some
mycobacteria.
Pseudomonas （假单胞菌属）and streptococci are
generally resistant.
The widespread use of these drugs in bowel
Clinical use : Preparation for elective surgery,
resulted in the selection of resistant organisms and
some outbreaks of enterocolitis in hospitals.
Cross-resistance between kanamycin and neomycin
is complete.
Neomycin & Kanamycin
Clinical Uses



Neomycin and kanamycin are now limited to
topical and oral use.
Neomycin is too toxic for parenteral(肠外)
use. parenteral administration of kanamycin
has also been largely abandoned.
Paromomycin(巴龙霉素):Effective against
visceral leishmaniasis when given parenterally,
and this serious infection may represent an
important new use for this drug.
Neomycin & Kanamycin
Adverse Reactions
All members of the neomycin group have significant
nephrotoxicity and ototoxicity.
Auditory function is affected more than vestibular
function. Deafness has occurred, especially in adults
with impaired renal function and prolonged elevation of
drug levels.
The sudden absorption of postoperatively instilled
kanamycin from the peritoneal cavity (3–5 g) has resulted
in curare-like neuromuscular blockade (箭毒样神经肌肉阻
滞 )and respiratory arrest. Calcium gluconate and
neostigmine can act as antidotes.
hypersensitivity: not common, prolonged application of
neomycin-containing ointments to skin and eyes has
resulted in severe allergic reactions.
Neomycin & Kanamycin
Kanamycin
Kanamycin has a more limited spectrum of
activity than Gentamicin has.
It is ineffective against Pseudomonas and most
gram-positive organisms.
Its clinical uses almost replaced by gentamicin.
Neomycin & Kanamycin
Neomycin新霉素
Spectrum of activity
Neomycin has a spectrum of activity similar to
that of kanamycin.
Untoward effects
Renal damage, eighth-nerve damage resulting in
nerve deafness.
Amikacin
Amikacin 阿米卡星, 丁胺卡那霉素
Specturm of activity of Amikacin
Amikacin has a spectrum of activity similar
to that of Gentamicin but often is reserved for
serratia (沙雷菌属）infections or for cases where resistance
to Gentamicin has emerged.
Clinical use
Intravenous; resistant to many enzymes that inactivate
gentamicin and tobramycin; higher doses and target peaks and
troughs than gentamicin and tobramycin
Adverse effects of Amikacin
Ototoxicity is the most serious side effect.
Spectinomycin(大观霉素 )


Spectinomycin is an aminocyclitol antibiotic that is
structurally related to aminoglycosides. It lacks
amino sugars and glycosidic bonds.
Intramuscular; sole use is for treatment of
antibiotic-resistant gonococcal infections or
gonococcal infections in penicillin-allergic patients
Polymyxins
Polymyxins 多粘菌素类
There are five polymyxins. A, B, C, D, E,
Polymyxin E, 多粘菌素E (Colistin,抗敌素)
is frequently used in clinics.
Polymyxins
Spectrum of activity

Polymyxins are active mainly against gram-negative
bacilli, particulary pseudomonas and coliform
organisms.
Mechanism of action of polymyxins
Polymyxins act by attaching to the cell membranes
of bacteria and other membranes rich in
phosphatidylethanolamin (磷脂酰乙醇胺) and
disrupting the osmotic properties and transport
mechanisms of the membrane. This results in
leakage of macromolecules and death of the cell.
Polymyxins


Polymyxins
Therapeutic uses Infections caused by
pseudomonas or coliform bacteria
resistant to other antimicrobial drugs.
Untoward effects




Neurotoxic effects
Polymyxin can cause paresthesias, dizziness
and incoordination.
Nephrotoxic effects
Some proteinuria(蛋白尿), hematuria （血尿）
are the evidence of tubular injury.
Part 5
Tetracyclines (四环素)&
Chloramphenicol(氯霉素)
Tetracyclines
Tetracyclines -Chemical structure
•Tetracycline (四环素)
Tetracyclines
Clinical used tetracyclines:

Tetracycline(四环素);

Demeclocycline(地美环素, 去甲金霉素);

Metacycline(美他环素, 甲烯土霉素);

Doxycycline(多西环素, 强力霉素);

Minocycline(米诺环素, 美满霉素).
(Antimicrobial activity enhanced from up to
down)

Tetracyclines
Tetracyclines -Overview
Crude product
Tetracycline(四环素),Chlortetracycline
(金霉素),Oxytetracycline (土霉素)
Semisynthetic derivative
Doxycycline(多西环素), Minocycline(米诺环素)
Antimicrobial activity
Tetracyclines
(1) Bacteriostatic
(2) Bactericidal (at high concentration )
(3) Minocycline > Doxycycline > Tetracycline
Antimicrobial spectrum
Broad-spectrum antibiotic
(1) Active against a wide range of aerobic and anaerobic gram-
positive and gram-negative bacteria.
(2) Effective against Rickettsia(立克次体）,Coxiella burnetii（螺旋
体）,Mycoplasma pneumoniae（支原体）,Chlamydia (衣原体), and
Plasmodium （疟原虫）.
(3) They are not active against fungi,virus.
Tetracyclines
Mechanism of action
(1) Enter bacteria by passive diffusion through the
protein channel formed by porin proteins of
outer cell membrane(G- organisms) and active
transport by an energy-dependent system that
pumps all tetracyclins across cytoplasmic
membrane (G+ organisms) .
(2) Inhibit protein synthesis in susceptible
microorganisms.
(3) Increase the permeability of the cell
membrane
Mechanism of action
Tetracyclines
Mechanism of
action:
①Chloramphenicol
②Macrolides,
Clindamycin
③Tetracyclines
•Inhibits binding of 30S
subunit with A site
•Interfering with the
binding of aminoacyl-tRNA
with aminoacyl site(A site)
Mechanism of resistance
Tetracyclines
(1) Decreased intracellular accumulation due to
either impaired influx or increased efflux by
a active transport protein pump.
(2) Ribosome protection that interfere with the
tetracycline binding to the ribosome.
(3) Enzyme inactivation of tetracycline.
ADME
Tetracyclines
(1) Absorption are impaired by food (except
doxycycline and minocycline ）
 Tetracyclines manly differ in their
absorption after oral administration.
(2) Distributed widely to tissue and body
fluid except for CSF.
(3) Excreted mainly in bile and urine.
(4) Tetracyclines across the placenta and are
also excreted in the milk.
(5) Bound to- and damage- growing bones
and teeth
As a result of chelation with calcium
Tetracyclines
Clinical Uses
(1)Rickettsial(立克次体) infections.
(2)Mycoplasma(支原体) infections.
(3)Chlamydia(衣原体) infection.
(4)Leptospira(螺旋体) infection.
(5)Bacterial infection.
Tetracyclines
Adverse reaction
(1)Gastrointestinal effects.
(2)Superinfections.
(3)Deposition of the drugs in growing
teeth and bones.
(4)Hepatic toxicity and renal toxicity.
(5)Photosensitivity.
(6)Pseudotumer cerebri(脑假瘤)
(7)Vestibular toxicity(前庭反应 )
Tetracyclines
Recent research
•Tetracycline and its derivatives doxycycline
and minocycline were found to have antiinflammatory and anti-apoptotic properties.
•Protect mice from brain ischemia, traumatic
brain injury, Huntington’s disease, etc.
•The mechanism partially though caspase-1, 3,
iNOS, COX-2 etc.
Tetracyclines
Tigecycline(替加环素)

A newly approved tetracycline analog,
tigecycline, is a glycylcycline(甘氨酰四环素类) and
a semisynthetic derivative of minocycline.
Tetracyclines



Tigecycline, the first glycylcycline to reach the clinic, has
several unique features that warrant its consideration apart
from the older tetracyclines. Many tetracycline-resistant
strains are susceptible to tigecycline because the common
resistance determinants have no activity against it.
Its spectrum is very broad. Coagulase-negative staphylococci
and Staphylococcus aureus, including methicillin-resistant,
vancomycin-intermediate, and vancomycin-resistant strains;
streptococci, penicillin susceptible and resistant; enterococci,
including vancomycin-resistant strains; gram-positive rods;
Enterobacteriaceae; multidrug-resistant strains of
Acinetobacter sp; anaerobes, both gram-positive and gramnegative; atypical agents, rickettsiae, chlamydia, and legionella;
and rapidly growing mycobacteria all are susceptible.
Proteus （变形杆菌）and P aeruginosa（铜绿假单胞菌）, however,
are intrinsically resistant.
Tetracyclines



Tigecycline, formulated for intravenous administration only, is given as a 100mg loading dose; then 50 mg every 12 hours. As with all tetracyclines, tissue
and intracellular penetration is excellent; consequently, the volume of
distribution is quite large and peak serum concentrations are somewhat
blunted. Elimination is primarily biliary, and no dosage adjustment is needed
for patients with renal insufficiency.
In addition to the tetracycline class effects, the chief adverse effect of
tigecycline is nausea, which occurs in up to one third of patients, and
occasionally vomiting. Neither nausea nor vomiting usually requires
discontinuation of the drug.
Tigecycline is FDA-approved for treatment of skin and skin-structure
infection and intra-abdominal infections. Because active drug concentrations
in the urine are relatively low, tigecycline may not be effective for urinary
tract infections and has no indication for this use. Because it is active
against a wide variety of multidrug-resistant nosocomial pathogens (eg,
methicillinresistant S aureus, extended-spectrum -lactamase-producing
gram-negatives, and Acinetobacter species), tigecycline is a welcome addition
to the antimicrobial drug group.
Chloramphenicol
Chloramphenicol (氯霉素)
Chemical structure
p 1246
p776pharm
Chloramphenicol
Antimicrobial activity
(1)Chloramphenicol
possesses
a
wide
antimicrobial spectrum.
(2) Primarily bacteriostatic , although it
may be bactericidal to certain species.
Chloramphenicol
Mechanism of action
Inhibit protein synthesis in susceptible
bacteria, and to a lesser extent, in
mammalian cell
2. Acts primarily by binding reversibly to
the 50 S ribosomal subunit
 Near the site of action of macrolides
and clindamycin, which it inhibits
competitively).
1.
Mechanism of action
Chloramphenicol
Mechanism of
action:
①Chloramphenicol
②Macrolides,
Clindamycin
③Tetracyclines
Mechanism of Resistance
Chloramphenicol
(1) Resistance usually caused by a
plasmid-encoded acetyltransferaes乙酰
转移酶 that inactive the drugs.
(2) The permeability of bacterial cell
membrane is changed.
Clinical uses
Chloramphenicol
(1) Bacterial meningitis.
(2) Typhoid fever(伤寒) and other types of
systemic Salmonella infections.
(3) Eye bacterial infection.
(4) Anaerobic infection.
(5) Rickettsial disease （立克次体病） and
brucellosis （布鲁杆菌病）, etc.
Adverse reactions
Chloramphenicol
(1)Hematological Toxicity:
 By dose-related toxic effect that presents
anemia, leukopenia and or thrombocytopenia
（血小板减少）
 By special response manifested by aplastic
anemia, leading in many cases to fatal
pancytopenia （全血细胞减少）.
(2) Toxicity for newborn infants:
 Gray baby syndrome(灰婴综合征).
(3)other reactions:
 hypersensitivity reaction, etc.
Drugs interactions

Chloramphenicol
Inhibits hepatic microsomal cytochrome
P450 enzyme, and thus may prolong the
t 1/2 of drugs that metabolized by this
system, e.g. warfarin, phenytoin, etc.
Part 6
Synthetic antimicrobial
agents(人工合成抗菌药)
Classification of
Synthetic antimicrobial agents
 Ⅰ. Quinolones(喹诺酮类);




Ⅱ. Sulfonamides(磺胺类);
Ⅲ. Other synthetic antimicrobial agents:
Trimethoprim (甲氧苄啶)
Nitrofurans (硝基呋喃类), etc.
Quinolones
Part6-1 Quinolones
General features
 Broad antimicrobial activity and are effective
after oral administration for the treatment
of a wide variety of infectious disease.
 Relatively few side effects.
 Microbial resistance to their action does not
develop rapidly.
Quinolones
Part6-1 Quinolones
Chemistry
•Derived from basic structure of nalidixic acid
(萘啶酸)and have substituents at N-1, C-5, C-7,
position 8 and a fluorine atom at position 6.
•Fluorine at position 6 enhances gyrase
inhibition and cell penetration.
Quinolones
Quinolones
Chemical structure
(萘啶酸)
(环丙沙星)
(诺氟沙星)
Classification
Generation
1 st (1962-1969)
2 nd (1969-1979)
3 rd (1980-1996)
4 th (1997-)
Quinolones
Examples
Nalidixic acid, 萘啶酸
Pipemidic acid 吡哌酸
Cinoxacin
西诺沙星
Norfloxacin
诺氟沙星
Levofloxacin 左氧氟沙星
Ciprofloxacin 环丙沙星
Ofloxacin 氧氟沙星
sparfloxacin 司帕沙星
Grepafloxacin 格帕沙星
Clinafloxacin 克林沙星
Gatifloxacin 加替沙星
Moxifloxacin 莫西沙星
Quinolones
Quinolones
First-generation agents(1962-1969)
Nalidixic acid, 萘啶酸
•The first generation drug of the quinolone
antibiotics
•Moderate gram-negative activity and minimal
systemic distribution
Clinical applications
• Uncomplicated urinary tract infections
Quinolones
Quinolones
Second-generation quinolones (1969-1979)
Pipemidic acid 吡哌酸
Cinoxacin西诺沙星
•Expanded gram-negative activity and atypical
pathogen coverage, but limited gram-positive
activity.
•Most active against aerobic gram-negative
bacilli
•Ciprofloxacin remains the quinolone most active
against Pseudomonas aeruginosa
Quinolones
Quinolones
Second-generation quinolones (1969-1979)
•Active against gram-positive and gramnegative bacteria, mycobacteria, mycoplasma支
原体and legionella species军团杆菌属.
•Longer half-lives due to slow elimination,
distribution into many tissues and body fluids
and penetration into human cells.
Quinolones
Quinolones
Third-generation quinolones (1980-1996
)
Norfloxacin 诺氟沙星，
Levofloxacin 左氧氟沙星，
Ciprofloxacin 环丙沙星，
Ofloxacin
氧氟沙星，
Sparfloxacin 司帕沙星
•Added potency against gram-negative
bacteria, anaerobes and mycobacteria.
•Retain expanded gram-negative and atypical
intracellular activity but have improved grampositive coverage
Quinolones
Quinolones
Fourth-generation agents (1997- )
Grepafloxacin 格帕沙星，Clinafloxacin 克林沙星，
Gatifloxacin 加替沙星，Moxifloxacin 莫西沙星
•Improve gram-positive coverage, maintain
gram-negative coverage, and gain anaerobic
coverage.
Quinolones
Quinolones
Antimicrobial activity & spectrum
(1) Bactericidal and have significant PAE.
(2)Excellent activity against aerobic gramnegative bacteria, some agents have
activity against Pesudomonas.
(3) Several newer agents with improved
activity against aerobic gram-positive
bacteria.
Quinolones
Quinolones
Antimicrobial activity & spectrum
(4) They also are effective against
Chlamydia spp.（衣原体）, Legionella
pneumophila(军团菌) ,anaerobic
bacteria, mycobacteria(分枝杆菌).
(5) Some agents have limited activity
against multiple-resistance strains.
(6) Bactericidal concentration≥
bacteriostatic concentration
Quinolones
Quinolones
Mechanism of actions
Topoisomerases : enzymes that control and
modify the topological states of DNA in cells.
• Topoisomerase I， III catalyse merely the
relaxation of DNA
• Topoisomerase II （DNA gyrase） catalyse
the supercoiling of DNA
• Topoisomerase IV involved in the separation
process of the DNA daughter chains after
chromosome duplication.
Quinolones
Quinolones
Mechanism of actions
The quinolone antibiotics target bacterial
• DNA gyrase (gram-negative bacteria)
and
• Topoisomerase IV (gram- positive
bacteria).
Mechanism of action
Quinolones
• Topoisomerase I,III
• Topoisomerase II,IV
Mechanism of action


Quinolones
The function of DNA gyrase is to introduce
supercoils into the linear DNA double helix, which
results in the highly condensed 3-dimensional
structure of the DNA usually present inside the cell.
DNA gyrase consists of two proteins (A and B), with
the active species being a heterotetramer (A2B2).
Mechanism of action
Quinolones
Mechanism of action
Quinolones
•The Gyr-A subunits were proposed to initially bind to
the double stranded DNA helix.
In an ATP-dependent process, described as
"intermediate gate opening step", both DNA strands are
cleaved at certain 4 base pair staggered sites.
•The 5'ends of the DNA chain are thereby bound
covalently to Tyrosin122 residues within the Gyr-A
subunits.
•Gyr-B subunits are probably responsible for the ATPdependent resealing process of the DNA.
Mechanism of action
Quinolones
•Topoisomerase IV: involved in the separation process
of the DNA daughter chains after chromosome
duplication.
•Unlike DNA gyrase, it is unable to catalyse the
supercoiling of DNA, merely its relaxation.
•The enzyme comprises two subunits, ParC and ParE.
•The ParC protein is homologous to the gyrase A
protein, while the ParE subunit is homologous to the
gyrase B protein.
Mechanism of action
Quinolones
•Inhibition of DNA gyrase →prevents the
relaxation of positively supercoiled DNA that
is required for normal transcription and
replication.
•Inhibition of topoisomerase IV →
interferes with separation of replicated
chromosomal DNA into the respective
daughter cells during cell division.
Quinolones
()
1
(-)
2
3
Model of the formation of negtive DNA
supercoils by DNA gyrase
The enzyme binds two segments of DNA (1), creating a node of
positive(+) superhelix. The enzyme then in-troduces a doublestrand break in the DNA and passes the front segment through
the break (2). The break is then resealed (3), creating a
negative(-) supercoil.
Quinolones inhibit the nicking and closing activity of the gyrase,
and also block the activity of toposomer-ase Ⅳ.
Quinolones
Mechanism of action
Quinolones inhibit the nicking and
closing activity of the gyrase
Quinolones
Resistance Mechanism
•Intrinsic resistance is rare
•With a frequency of about one in 107–
109, especially among staphylococci,
pseudomonas, and serratia沙雷(氏)菌.
Quinolones
Resistance Mechanism
(1) Mutation of the gyrA gene that encoded
the A subunit polypeptide can confer
resistance to these drugs.
(2) Mutation of the gene cfxB and nfxB that
encoded the porin decreased permeability
of cell membrance.
(3) The high expression of norA gene
(encoded active pump protein) increased
drugs efflex by a active transport protein
pump.
(4) Plasmid mediated resistance.
Quinolones
ADME of Quinolones
(1) Well absorbed after oral
administration.
(2) Distributed widely in body
tissue, even in CSF.
(3) Excreted mainly in urine.
 Routes of elimination differ
among the Quinolones.
Clinical Uses
Quinolones
（1）Urinary tract infections.
 The main indication for quinolones
 In the treatment of uncomplicated and
complicated UTIs, cure rates can exceed
90% and 80%, respectively.
 Potent agents to use against Haemophilus
ducreyi (软性下疳嗜血杆菌) and penicillinsensitive and penicillin-resistant Neisseria
gonorrhoeae淋(病双)球菌.
Clinical Uses
Quinolones
(2) GI and abdominal infections.
• Excellent in vitro activity against many
enteric pathogens, including Escherichia coli
大肠杆菌, Aeromonas气单胞菌属, Shigella志贺
(氏)杆菌, Salmonella沙门氏菌, Campylobacter
弯曲杆菌属, Vibrio弧菌属, and Yersinia
species耶尔森菌
• Furthermore, quinolone drug concentrations
in feces are exceedingly high.
Clinical Uses
Quinolones
(3) Respiratory tract infections.
 Have inferior activity against
streptococci链球菌and should not be
used as primary therapy for common
upper respiratory tract infections.
 Alternatives for treatment of acute
exacerbation of chronic bronchitis in
patients with obstructive pulmonary
disease who are intolerant of or have
developed resistance to first-line
antibiotics.
Clinical Uses

Quinolones
antibiotics with activity against
Streptococcus pneumoniae,
Haemophilus influenzae流感(嗜血)杆菌,
and Moraxella catarrhalis粘膜炎莫拉菌.
(4) Other infections： Bone, joint and
soft tissue infections.
Adverse reactions
Quinolones
(1)Gastrointestinal effects.
 The most common reactions
(2)CNS side effects.
 Penetrate BBB→ GABA↓
(3)Allergic reaction.
 Skin rashses, itchs, angioneuroedema , etc.
 Photosensitivity
(4)other effects.
 Cardiac toxicity： Q-T interval↑
 Liver and renal injury
Adverse reactions
Quinolones
(4)other effects.
 Muscle skeletal system
 Amyasthenia 肌无力, myosalgia肌痛,
joint pain and inflammation
 Increase intracranial pressure in
infants
Quinolones agents
Pipemidic acid (吡哌酸)
 Norfloxacin (诺氟沙星)
 Ciprofloxacin (环丙杀星)
 Ofloxacin（氧氟沙星）
 Levofloxacin（左氧氟沙星）
 Lomefloxacin（洛美沙星）
 Fleroxacin（氟罗沙星）
 Sparfloxacin（司帕沙星）

Quinolones
Pharmacokinetic Properties of Fluoroquinolones
Quinolones
喹诺酮类研究两大动向

继续研发第四代氟喹诺酮



近年上市的:吉米沙星(gemifloxacin ),巴洛沙星
目前正在研发中的:西他沙星(sitafloxacin ),奥鲁沙
星 (olamufloxacin )。
注意研究结构变幅更大的喹诺酮


近年上市的帕珠沙星(pazufloxacin )、鲁利沙星
(prulifloxacin )
非氟喹诺酮格林沙星(garenoxacin )
Part6-2 Sulfonamides
Sulfonamides
Sulfonamides
Sulfonamides
Antimicrobial activity
(1) Sulfonamides have a wide range
of antimicrobial activity.
 G+,G- bacteria, Nocardia 诺卡菌属,
Bedsonia trachomatis沙眼衣原体, etc.
 Enteric bacteria etc. less effective
 Rickett's organism
(2) Sulfonamides exert only
bacteriostatic effect.
Sulfonamides
Mechanism of action
 Structural
analogs and
competitive antagonists of
para-aminobenzoic acid (对氨基
苯甲酸 PABA)
 Prevent normal bacterial
utilization of PABA for the
synthesis of folic acid.
Sulfonamides
Mechanism of action
Sulfonamides
Mechanism of Resistance
 Originate
by random mutation
and selection or by transfer
of resistance by plasmides.
 Such resistance usually is
persistent and irreversible.
Sulfonamides
Mechanism of Resistance
The resistance characterized by:
(1)A lower affinity for sulfonamides by
the dihydropteroate synthase
(2)Decreased cell permeability or active
efflux of the drug
(3)An alternative pathway to synthesis
the essential metabolites
(4)An increased production of essential
metaboltes
Sulfonamides
Classification
(1) Oral absorbable agents
 Short-acting agents
 Medium-acting agents
 Long-acting agents
(2) Oral nonabsorbable agents
(3) Topical agents.
(4) Combination agents.
Clinical uses
Sulfonamides
(1) systemic infections.
 cerebral meningitis
 Tympanitis 中耳炎
 Uncomplicated urinary tract infections
 Combined with TMP in treating complicated
urinary tract infections,respiratory
infections,GI infections
(2) intestinal infections.
 Sulfasalazine 柳氮磺吡啶
(3) infections of burn and wound.
 Sulfadiazine sliver(磺胺嘧啶银)
Sulfonamides
Adverse reactions
(1)Urinary tract disturbances
(2)Hypersensitivity reaction
(3)Hematopoietic system
disturbances↓
(4)Kernicterus 脑核黄疸
 caused by bilirubin胆红素 replacment
(5)Hepatitis
(6)GI disturbances
Sulfonamides
ADME of sulfonamides
(1) Approximately 70%-100% of an
oral dose is absorbed.
(2) Sulfonamides are distributed
throughout all tissues of the body,
even in CSF
 Sulfadiazine磺胺嘧啶and sulfisoxazole
磺胺异恶唑, may be effective in
meningeal infections .
(3) Sulfonamides readily pass though
the placenta.
Sulfonamides
ADME of sulfonamides
(4) Sulfonamides are metabolized in the
liver by acetylation.
(5) Sulfonamides eliminated mainly in
the urine as the unchanged drug and
metabolic product.

In acid urine, the eliminated are
insoluble and may precipitate, thus
induced renal disturbance.
Sulfonamides
Drugs interactions


Increase the effects of tolbutamide
甲苯磺丁脲, warfarin , trexan甲氨喋呤
The reason is: all sulfonamides are
bound in varying degree to plasma
protein.
Sulfonamides
Sulfonamides Agents
(1) Oral absorbable agents
 Short-acting agents
Sulfafurazole(SIZ,菌得清)
Sulfadimidine,(SN2,磺胺二甲嘧啶)
 Medium-acting agents
Sulfadiazine(SD,磺胺嘧啶)
Sulfamethoxazole(SMZ,新诺明)
 Long-acting agents
Sulfamonomethoxine(SMM，磺胺间甲氧嘧啶)
Sulfonamides
Sulfonamides Agents
(2) Oral nonabsorbable agents
Sulfasalazine(柳氮磺吡啶 )
(3) Topical agents.
Mafenide(SML, 磺胺米窿)
Sulfadiazine sliver(磺胺嘧啶银)
Sulfacetamide(SA,磺胺醋酰）
Sulfonamides
Sulfonamides Agents
(4) Combination agents.
 Co-trimoxazole(复方新诺明）



Trimethoprim(甲氧苄啶) in combination
with Sulfamethoxazole(1:5) exerts a
synergistic effects.
Pharmcokinetics: The ADME of the two
agent is similar.
Pharmcodynamics: Co-block essential
enzymes of folate metabolism.
Sulfonamides
Sulfonamides Agents
(4) Combination agents.
 Co-trimoxazole(复方新诺明）
Clinical Use



Chronic and recurrent infections in the urinary tract
Bacterial respiratory infections
GI infections (eg. induced by Salmonella)
Adverse reaction


There is no evidence that co-trimoxazole, when given in
recommended dose, induced folate deficiency in normal
persons.
The main untoward effects is hypersensitive reactions( eg.
involve the skin).
Other Synthetic antimicrobial

Trimethoprim (甲氧苄啶)
Dihydrofolate reductase inhibitor
Drug resistance occurs easily when used
alone
Nitrofurans (硝基呋喃类)
Nitrofurantoin(呋喃妥因）
Bactericidal agent
Co A inhibitor→DNA damage
Resistance is rare

Clinical applications: Urinary tract infections




Other Synthetic antimicrobial
Trimethoprim(甲氧苄啶)
 Nitrofurans(硝基呋喃类):

Funacillin(呋喃西林)

Furantoin(呋喃妥因)

Furazolidone(呋喃唑酮, 痢特灵)

END OF CLASS