Download Aminoglycosides（氨基糖苷类）

Aminoglycosides（氨基糖苷类）,
Macrolides（大环内酯类）and others
2011.12
Aminoglycosides（氨基糖苷类）
Tuberculosis, still severe infection now
1882, Heinrich Hermann Robert Koch
discovered M. tuberculosis （结核分枝杆菌）
1940’s, Merck supported S.A. Waksman’s lab,
Rutgers university, NJ
1940, actinomycin（放线菌素）, toxic
1942, streptothricin （链丝菌素），still toxic
1942, Albert Schatz, PhD student
Aminoglycosides（氨基糖苷类）
1943.6 returned from
army
Oct 19, 1943，
streptomycin isolated
1944, Mayo clinic
1946, graduated and
patent left in Rutgers
1947, succeeded in
TB treatment
Law suit
1952, Nobel Prize to
Waksman
Streptomycin（链霉素）
Individual aminoglycosides
Streptomycin（链霉素）
Gentamycin（庆大霉素）
Amikacin（氨苄卡星）
Tobramycin（妥布霉素）
Netilmycin（奈替米星）
aminoglycosides
Common characters:
 Potent effect on Gram- bacteria, including
Pseudomonas, Mycobacterium tuberculosis
 Ineffective against anaerobic bacteria
 Not absorbed orally
 Untoward effects: >5 days; high dose; elderly; renal
insufficiency
ototoxicity（2％-10％）: vertigo（眩晕）, ataxia（共
济失调）, loss of banlance
nephrotoxicity（6％-10％）
neuromuscular blocking (co-administered with
general analgesics or muscle relaxants)
Toxicity
Their undesirable side effects: severe ototoxicity and
nephrotoxicity.
18 of 21 actress showing “qianshou guanyin” were caused
deafness by aminoglycosides.
小囊
球囊
耳蜗
水平半规管
血管纹
前庭阶
中阶；蜗管
鼓阶
aminoglycosides
Mechanism:
binding to the S12 Protein of the 30S subunit
of the bacterial ribosome, interfering with
the binding of formyl-methionyl-tRNA to the
30S subunit
Resistance to aminoglycosides
aminoglycoside-modifying enzymes (钝化酶)
 Phosphoryltransferases（磷酰转移酶）
 Acetyltransferases（乙酰转移酶）
 Adenylyltransferases（腺苷酰转移酶）
Polymyxins 多黏菌素
Polymyxins（多粘菌素类）
Cyclic peptide with a long hydrophobic tail
polymyxins
detergents, selectively toxic for Grambacteria due to their specificity for the
lipopolysaccharide（脂多糖） molecule
strong nephrotoxic
renewed interest duo to antimicrobial
resistance
Macrolides（大环内酯类）
Macrolides（大环内酯类）
1949, Abelardo Aguilar
soil samples to Eli Lilly
Erythromycin from
Streptomyces erythreus
（红色链霉菌）
1952, clinical uses
1970’s, clarithromycin
（克拉霉素），acid
instability overcome
azithromycin, …
Erythromycin
红霉素
O
N
OH
OH
OH
OH
N
O
O HO
O
O
O
O
OH
OH
O
N
O
O
O HO
O
OH
O
O
N
O
OH
O
O
OH
O
ÂÞºì ùËØ¡¡ Roxithromycin
OH
OH
O
OH
O
O
O HO
O
O
HN
OH
OH
O
O HO
O
OH O
O
N
OH
O HO
O
O
O
O
Erythromycin Oxime
O
OH
O
Dirithromycin
O
O
OH
O
O
N
O
N
O
Beckmann
Rearraangement
OH
O
N
N
OH
HN
OH
OH
OH
OH
OH
»¹ Ô-
N
O
O
OH
O HO
O
O
N
O
¼×»ù»¯
O
O HO
O
O
O
O
O
OH
O
OH
°¢Æë
ùËØ¡¡ Azithromycin
macrolides
Antibacterial spectrum:
 similar or wider anti-bacterial spectrum
than penicillin (replacing penicillin for
allergic patients)
 some G- bacteria: Legionella pneumophila
（嗜肺军团菌），now >50 lines, >70 serum
types
 Mycoplasma pneumoniae （肺炎支原体）
Legionella pneumophila （嗜肺军团菌）
Mechanism of macrolides
binding to the 50s subunit of the bacterial
70s rRNA complex
→interfering with aminoacyl translocation
→preventing the transfer of the tRNA bound
at the A site of the rRNA complex to the P
site of the rRNA complex
Resistance to macrolides
Reduced permeability of the cell membrane
or active efflux
Production of esterases that hydrolyze
macrolides
Modification of the ribosomal binding site by
chromosomal mutation or by a macrolideinducible or a constitutive methylase
Clinical uses of macrolides
First choice:
Legionaire’s disease（军团病）
diphtheria（白喉），eradicated through
widespread vaccination
1976.7，费城一旅馆退伍军人会议
近200人罹患前所未见呼吸道感染，29人死
全身不适、头痛、恶心呕吐、腹泻、肌肉疼痛、
发烧、咳嗽。干咳，渐咳灰色或血色浓痰，死于
肺炎及其他并发症
数月调查，耗200万美元
鉴定：嗜肺军团菌（源于首次在退伍军人发现）
空调系统的水箱、管道是该菌的理想繁殖地
Clinical uses
mycoplasmal pneumonia（支原体肺炎），小
儿多见
chlamydial Infection（沙眼衣原体、鹦鹉热衣
原体感染）：沙眼、性病性淋巴肉芽肿
Azithromycin（阿奇霉素）：mostly replacing
erythromycin
Lincomycin（林可霉素）
Lincomycin（林可霉素）
clindamycin
lincomycin （林可霉素）
Actinomyces Streptomyces lincolnensis
Mechanism, spectrum,
uses and untoward effect of clindamycin





Mechanism, spectrum and structure similar to erythromycin
Also effective against other species as well i.e. actinomycetes（放
线菌）, mycoplasma（支原体）, and some species of Plasmodium
（疟原虫）
reserved for patients who are either allergic to penicillin or where
bacteria has developed resistance
Anaerobic infections
Sensitive gram-positive bacteria infections (first choice for S.
aureus induced osteomyelitis（骨髓炎）
malaria
acne（痤疮）
methicillin-resistant Staphylocuccus aureus (MRSA) infections（耐
甲氧西林金黄色葡萄球菌感染）
untoward effect: Clostridium difficile （艰难梭菌 ）-associated
diarrhea (main cause of pseudomembraneous colitis, 假膜性肠炎)
Methicillin-resistant Staphylococcus aureus (MRSA)
Tetracyclines 四环素类
1945, Benjamin
Duggar, Aureomycin
（金霉素）
1950， Lloyd
Conover (Pfizer),
tetracycline
Tetracycline（四环素）
tetracyclines
Sources: Actinobacteria, Streptomyces genus
（链霉菌）
natural:
oxytetracycline（土霉素）, seldom used
tetracycline（四环素）, seldom used
semi-synthetic:
doxycycline（多西环素）
minocycline（米诺环素）
metacycline（美他环素）
Minocycline（米诺环素）
Doxycyclne（多西环素）
Pharmacokinetics of tetracyclines
deposited and staining developing teeth
(even when taken by the mother during
pregnancy)
causing permanent teeth discoloration
(under children of 8)
Antibacterial spectrum
Antibacterial spectrum wide, but most of
microorganisms resistant to tetracyclines
now
Mechanism
Bacterial – 70S (50S/30S)
Mammalian – 80S (60S/40S)
• High levels may
interact with mammalian
ribosomes
Binding to 30s subunit
• Aminoglycosides
• tetracyclines
Binding to 50s subunit
• chloramphenicol
• Macrolides,
erythromycin,
clarithromycin,
azithromycin, …
30s subunit
mRNA
50s subunit
protein
Clinical uses
first-line（一线）:
 Rocky Mountain spotted fever (Rickettsia)落基山斑
疹热
 (Coxiella burnetii，科克斯属立克次体 ) Q fever
 (Chlamydia) Psittacosis（鹦鹉热）
Lymphogranuloma venereum(性病淋巴肉芽肿)
 eradicating nasal carriage（鼻腔带菌） of
meningococci（脑膜炎球菌）
 acne（痤疮）；rosacea（酒糟鼻）
Since wide resistance to tetracyclines, not used often
Coxiella burnetii
四环素牙
Chloramphenicol（氯霉素）
Streptomyces
Venezuelae,
isolated by
David Gottlieb
1949,
introduced into
clinical
practice
First synthetic
antibiotic
Chloramphenicol（氯霉素）
chloramphenicol
wide spectrum
Gram-positive bacteria (including most
strains of MRSA)
Gram-negative bacteria
anaerobes
potent inhibitor of the cytochrome P450
isoforms CYP2C19 and CYP3A4
Mechanism and resistance
binding to 50S ribosomal subunit
preventing the docking of amino-acylated tRNA
Bacterial resistance:
reduced membrane permeability
mutation of the 50S ribosomal subunit
chloramphenicol acetyltransferase
protein synthesis inhibitors
Bacterial – 70S (50S/30S)
Mammalian – 80S (60S/40S)
• High levels may
interact with mammalian
ribosomes
Binding to 30s subunit
• Aminoglycosides
• tetracyclines
Binding to 50s subunit
• chloramphenicol
• Macrolides,
erythromycin,
clarithromycin,
azithromycin, …
30s subunit
mRNA
50s subunit
protein
Therapeutic uses
Originally, typhoid（伤寒）
Now, Staphylococcal and other
bacterial brain abscesses（脓肿） and
meningitis（脑膜炎）
Vancomycin-resistant enterococcus
infections
Adverse drug effects
Aplastic anemia（再生障碍性贫血）：
1/30000－1/50000
Idiosyncratic 特发性; unrelated to dose
Gray baby syndrome: lack of glucoronyl
transferase （葡糖醛酸转移酶）
Linezolid 利奈唑胺
Linezolid（利奈唑胺）
discovered in the 1990s
approved for use in 2000
first oxazolidinone（噁唑烷酮 ） antibiotic
linezolid
effective against all clinically important
Gram-positive bacteria (including
vancomycin-resistant enterococci and
methicillin-resistant Staphylococcus aureus,
etc.
2005, 中国细菌耐药监测网:金葡菌感染患者
MRSA分离率占69.2%。
Simplified schematic of mRNA translation. Linezolid occupies
the A site (at center) and prevents tRNA from binding.
Linezolid binds to the 23S portion of the 50S subunit