b-????

1
???
???
??????????
????
??? ????
???????
???? ???
??? ????? ????? ???
???????
b-???? ????
2
???????

• ????? Aminoglycosides
• ??? Tetracyclines
• ???? Macrolides
• ??? Chloramphenicol

3
????? Aminoglycosides
4
Normal bacterial cell
Aminoglycoside-treated bacterial cell
5
??????

• ??? streptomycin
• ?? ?????????G??G-??
• ??????????
• ???????????---???????(?penicillin?vancomycin??)
• ???????
• ??????(????(tetracycline)??)

6
??????

• ???? gentamicin
• ????,?????
• G-???????????????????????????????(Pseudomonas
  aeruginosa)
• G????????????????????
• ?????G-???
• ???????????

7
??????

• ????
• ??????????????????????????---gt??????
• ???????(????)?????
• ??????
• ??????????????????,????????????????????????
• neomycin?amikacin?kanamycin---gt???????,streptomyci
  n?gentamicin--gt???????????

8
??????

• ????????,??
• neomycin?tobramycin?gentamicin?kanamycin?netilmyci
  n???????

• ???????????,??????????????????????????????

• Streptomycin????,?????,???????

9
??????

• ??????????????????

• ??---gt????---gt?????????????????---gt??

• ??????????,?????????????????????

10
????? Macrolides
??????

• ???????50S?????????????????

• ???????????????

Erythromycin R1 CH3, R2H Clarithromycin
R1, R2 CH3
11
???? Tetracyclines
???,30S???????????
???????????

• ???????--???????,??--???????

• ????????????--???6?????

• ???????---???

• ??????????????

12
??? Chloramphenicol ???? Thiamphenicol
?50s????????
?????

• ??????
• ????????????

• ????????????---??

• ?vancomycin?????????????

• ??????--????

13
???????,????
???????????

• ???????????
• ????????????
• ?????
• ?????????????

14
Site of action
Drugs
Target
cell wall
penicillins
transpeptidase
peptidoglycan
cephalosporins
transpeptidase
vancomycin
acyl-D-alanyl-D-alanine
teicoplanin
acyl-D-alanyl-D-alanine
ribosome
chloramphenicol
peptidyl transferase of 50S subunit
clindamycin
50S ribosomal subunit transpeptidation
macrolides
50S ribosomal subunit
tetracyclines
ribosomal A-site
aminoglycosides
initiation complex and translation
fusidic acid
elongation factor G
nucleic acid
quinolones
DNA gyrase
metronidazole
DNA strands
rifampicin
RNA polymerase
folic acid
sulfonamides
pteroic acid synthetase
synthesis
trimethoprim
dihydrofolate reductase
15
Mechanism Of Resistance To Antibiotics
Altered Targets Decreased Accumulation Decreased Accumulation Enzymatic Inactivation of Drug
Altered Targets Permeability Decreased Efflux Increased Enzymatic Inactivation of Drug
?????
????
?????
B-????
?????
???
????
?????
16
???
???
??????????
????
??? ????
???????
???? ???
??? ????? ????? ???
???????
b-???? ????
17
????? Antituberculosis Drugs
??????? ????????????????
18
??????Mycobacterium tuberculosis

• ???
• ?????
• ???
• ???
• ??????

????
19

• ???????
• 20?????????
• ??????2000?
• ???????1000?
• ????300?????????30?????
• ???2/3????????MDR???
• WHO??????????

20
1949? ????15????????85??,???????1.750

• ?????????????
• ????3.67
• ????????????1.6

21

• ????
• ???????3.3?
• ?????????590 ??
• ???????200??
• ?????15- 25??
• ??22???????????,????,?????
• ???????
• ???150?????/??
• ???????65??
• MDR??????28-41

22

• ????????????
• ??????????????????
• ?????(multiple drug resistance)??????,?????????
• ????????????

23

• ???
• ??(DR)?????(MDR)????
• ??????????
• 1991????14???????????
• ?????W?????????????
• ????????????4060??
• ??????????????80
• MDR???????????

24

• 1994?WHO????????????????????(??3?)
• 35??????????HR
• ?????????????MDR?????214
• ???????????????????
• ???????????

25

• ?????????????????????30?
• ?????????????????
• ?????????????????????????40
• ?????????????????????????
• ??????????????????
• ????????????????????

26

• ????????
• ????????
• ?????????????????????
• ????????
• ????????
• ?????????????????????????????????????????
• ?????????????????????????????????,???????????,??
  ???????????

27
??? isoniazid
???????????

• ?????????
• ???????????????
• ?????????,?????????????????
• ???????

??????????????
28

• ??????????(mycolic acid)?????,????????????????,
  
• ???(??prodrug)
• ?????????-?????(mycobacterial catalase-peroxidase
  ,KatG)??
• ??????????????(acyl carrier protein
  ,AcpM)?ß-??????????(beta-ketoacyl carrier
  protein synthetase ,KasA)???????
• ??????????

29

• ??????????????????
• ??????????????????
• ??????????????(???????isoniazid????????)
• ????????
• ???isoniazid????????
• ??????????mycolic acid?????inhA????????(missense
  mutation)

30
???(rifampin)
??????(Streptomyces mediterranei)???????(rifamyci
n )?????
??????

• ?????????
• ??????isoniazid?????
• ?????????????????
• ???????
• ???????????
• ??????

31

• Inhibit Nucleic Acid Synthesis

Pteridine p-Aminobenzoic acid
Dihydropteroate synthetase
Dihydropteroic acid
Dihydrofolic acid
Nitroimidazoles
Dihydrofolate reductase
???
Quinolones
Tetrahydrofolic acid
-
-
DNA Gyrase
Supercoiled DNA
Purines Pyrimidines
Relaxed DNA
32
????(ethambutol)

• ???????,?pH???????
• ????????
• ?????????,???
• ???????????
• ??????

33
????(pyrazinamide)

• ??????????
• ???isoniazid?????rifampin?
• ?????????,??????
• ??????????????
• ??????????
• ????????????
• ???,???????????????

34

• ??????
• ????????,?????????
• ?????????????????????
• ?????????????
• ????????????????????
• ???
• 2???-???-????-???/4???-???
• ?2???-???-????- / 4???-???
• ??6?????