1. BlockⅤ: pharmacology Chemotherapeutic drugs (化学治疗药物)
汤慧芳
Tel:

2. (1)Chemotherapy(化学治疗, 简称化疗) (2)Chemotherapeutic drugs:
Antimicrobial drugs(抗微生物药);
Antiparasitic durgs(抗寄生虫药);
Antineoplastic drugs(抗肿瘤药).
(3)Antimicrobial drugs:
Antibacterial drugs(抗菌药);
Antifungal drugs(抗真菌药);
Antiviral drugs(抗病毒药).

3. Contents Part 1. General considerations of anti-microbial agents
Part 2. -Lactam antibiotics
Part 3. Macrolides (大环内酯类), lincomycins (林可霉素类), and vancomycins (万古霉素)
Part 4. Aminoglycosides (氨基糖苷类) & polymyxins(多黏菌素类)
Part 5. Tetracyclines(四环素类)& chloramphenicol(氯霉素)
Part 6. Synthetic antimicrobial agents(人工合成抗菌药)
Part 7. Antituberculous drugs & antileprotic drugs
Part 8. Antifungal agents & Antiviral agents
Part 9. The drugs treated parasitic infections

4. Antimicrobial drugs classification
According to bioactivity
Anti G+ antibiotic
Anti G- antibiotic
Broad-spectrum antibiotic
Anti mycobacterium（分支杆菌） antibiotic
Anti anaerobe（厌氧菌） antibiotic
β- lactamase inhibitor

5. History of Antimicrobial Therapy
1909 Ehrlich discovers Salvarsan（撒尔佛散，治疗梅毒特效剂）
“Magic bullet” for treatment of syphilis（梅毒）
1928 Fleming discovers penicillin(青霉素)
1932 Domagk discovers sulfonamides（磺胺类药物）
1940s Penicillin and streptomycin （链霉素）used widely, cephalosporins （头孢菌素）discovered
1947 Chloramphenicol （氯霉素）discovered, first broad spectrum agent
1950s Tetracycline （四环素）in use
1952 Erythromycin （红霉素）discovered (macrolides大环内酯类)
1956 Vancomycin （万古霉素）used for penicillin-resistant S. aureus
1957 Kanamycin（卡那霉素） discovered (aminoglycosides氨基苷类)
1962 Nalidixic acid （萘啶酸）discovered (quinolones喹诺酮类)
1980s Fluoroquinolones（氟喹诺酮类）, broad spectrum cephalosporins
2000s Newer agents to combat resistant pathogens
There is a very long history that people discovered many drugs to fight against microbes that cause diseases, but we haven’t got the final victory. Since, both microbes and cancer cells can evolve resistance to drug therapies.

6. These situations have severely limited therapeutic options in the treatment of life-threatening infection. E.g., multi-drug resistance Tuberculosis is more terrible than cancer, since it can propagate.

10. General considerations of antimicrobial agents (抗微生物药物概论)
Part-1
General considerations of antimicrobial agents
(抗微生物药物概论)

11. Contents 1. Overview 2. Term and definition
3. Classification and mechanism of antibacterial action
4. Bacterial resistance

12. Antimicrobial drugs: 1. Overview: Antibacterial drugs(抗菌药);
Antifungal drugs(抗真菌药);
Antiviral drugs(抗病毒药).

13. The relationship of the host, microorganisms, antimicrobial drugs.
Adverse effects
Resistance
Pharmacokinetics
Therapeutic Effects
pathogenicity
Interactions between drug , human body, and pathogens is complex.
Immunological
responses

14. Terminology 1. Antibacterial drugs(抗菌药) 2. Antibiotics(抗生素)
3. Bacteriostatic drugs(抑菌药)
4. Bactericidal drugs(杀菌药)
5. Antibacterial spectrum(抗菌谱)
6. Chemotherapetic index (化疗指数,CI)
7. Minimum inhibitory concentration (最小抑菌浓度, MIC)
8. Minimum bactericidal concentration (最小杀菌浓度, MBC)
9. Concentration Dependent killing
10. Post antibiotic effect (抗生素后效应,PAE)
11. Time-dependent killing
There are many terms to describe the antimicrobes properties.

15. 2. Terms and definition: (1)Antibacterial drugs(抗菌药):
Substances that can kill bacteria and/or inhibit its growth.
including:
①Antibiotics(抗生素);
②Synthetic antimicrobial agents, such as sulfonamides(磺胺类) and quinolones(喹诺酮类), etc.

16. Terms and definition
(2)Antibiotics(抗生素):
Substances produced by various species of microorganisms(bacteria, fungi, actinomyces, etc.), which can kill other microorganisms or inhibit their growth.

17. (3)Chemotherapetic index: LD50/ED50, or LD5/ED95
Terms and definition
(3)Chemotherapetic index:
LD50/ED50, or LD5/ED95
(4)Antibacterial spectrum(抗菌谱);
(5)Bacteriostatic drugs(抑菌药);
(6)Bactericidal drugs(杀菌药);

18. Terms and definition
agents

19. (7)Minimum inhibitory concent-ration(MIC);
Terms and definition
(7)Minimum inhibitory concent-ration(MIC);
(8)Minimum bactericidal concen-tration(MBC):
MBC ≥ MIC;
if MBC > 32 times MIC  resistance.

20. Antimicrobial Susceptibility Testing
7.Minimum inhibitory concentration (MIC)
The lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation
Used by diagnostic laboratories mainly to confirm resistance, but most often as a research tool to determine the in vitro activity of new antimicrobials, and data from such studies have been used to determine MIC breakpoints.
8. Minimum bactericidal concentration (MBC)
The lowest concentration of antimicrobial that will prevent the growth of an organism after subculture on to antibiotic-free media.
MBC determinations are undertaken less frequently and their major use has been reserved for isolates from the blood of patients with endocarditis
7. Minimum inhibitory concentration (MIC)
8. Minimum bactericidal
concentration (MBC): 99.9% decrease in growth over 24 hours

21. Incubate 18 to
24 hr at 37℃
Measure
diameters of
nongrowth
zones
Disk diffusion method for testing bacteria for susceptibility to specific antimicrobial drugs.

22. Terms and definition
9. Concentration Dependent killing: situation in which the bactericidal activity of a drug depends by how much the drug concentration exceeds the Minimum inhibitory concentration of the organism in question. e.g. aminoglycosides and quinolones
10. Time-dependent killing: situation in which the bactericidal activity of a drug depends how long the drug concentration exceeds the Minimum inhibitory concentration of the organism in question. e.g. -lactams and vancomycin
11. Post antibiotic affect (PAE) : Persistence of suppression of bacterial growth after limited exposure to an antimicrobial agent. e.g. aminoglycosides
11. Post antibiotic effect (PAE)
Refers to a period of time after complete removal of an antibiotic during which there is no growth of the target organism
Several factors influence the presence or duration of the PAE including the type of organism, type of antimicrobial, concentration of antimicrobial, duration of antimicrobial exposure, and antimicrobial combinations.

23. Classification and mechanism of antibacterial action:
(1) inhibit synthesis of bacterial cell walls;
(2) act directly on the cell membrane of the microorganism and affect its permeability, and leading to leakage of intracellular compounds;
(3) inhibit protein synthesis;
(4) affect bacterial nucleic acid metabolism;
(5) The anti-metabolites of folic acid, that can block essential enzymes of folic acid synthetic metabolism.

24. Classification and mechanism of action① ④ ⑤ ③ ②

25. Classification and mechanism of action
(1)Inhibiting synthesis of bacterial cell walls:
UDP-乙酰胞壁酸-5肽
双糖十肽聚合物

26. Classification and mechanism of action
-Lactam antibiotics
vancomycin
transpeptidase

27. Classification and mechanism of action
(2)Affecting permeability of membrane:
①Ionic-adsorbed(streptomycin);
②binding to ergosterol(amphotercin B);
③Inhibiting the synthesis of ergosterol (imidazoles);
④Surface-active agent, that interact strongly with phospholipids(polymixins).

28. Classification and mechanism of action
(3)Inhibiting protein synthesis:
affecting the function of 30S：streptomycin, Tetracyclines(四环素类)
affecting the function of 50S：
streptomycin, Macrolides (大环内酯类), lincomycins, chloramphenicol etc.

29. Inhibiting protein synthesis
利奈唑胺
氨基苷类
氨基苷类
氨基苷类
四环素类
氯霉素类
大环内酯类
林可霉素类

30. Classification and mechanism of action
(4)Affecting bacterial nucleic acid metabolism: quinolones, etc.

31. Pteridine(蝶啶) + PABA(对氨苯甲酸) Blocked by sulfonamides
Classification and mechanism of action
(5)Blocking enzymes of folate metabolism:
Pteridine(蝶啶) + PABA(对氨苯甲酸)
Dihydropteroate
synthase
Blocked by sulfonamides
Dihydropteroic acid(二氢蝶酸)
Glutaminic acid
Dihydrofolic acid(二氢叶酸)
NADPH
Dihydrofolate
reductasease
Blocked by trimethoprim
NADP
Tetrahydrofolic acid(四氢叶酸)

32. Bacterial Resistance

33. 4. Bacterial resistance:
(1)Category of resistance:
①Intrinsic resistance:
Inherent features
usually expressed by chromosomal genes
②Acquired resistance:
emerge from previously sensitive bacterial populations
Caused by mutations in chromosomal genes
Or by acquisition of plasmids or transposons

34. (2)Mechanism of bacterial resistance:
①Enzymatic inactivation and modification;
②to inhance active efflux system:
③Decreased permeability;
④Target alteration;

35. Mechanism of bacterial resistance
①To produce inactivated enzyme: IM OM
Penicillin
b-lactam
Penicillinase
Inactive
Kanamycin
Acetylation
Phosphorylation
Adenylyation
1B. Enzymatic modification
e.g. Aminoglycoside modification
1A. Enzymatic inactivation
e.g. b-lactamase

36. Mechanism of bacterial resistance
② To enhance active efflux system(主动外排系统):

37. Mechanism of bacterial resistance
③ Decreased permeability :
Absence of, mutation in, or loss of the appropriate porins(膜孔蛋白) channel can slow the rate of drug entry into the cell, or prevent entry altogether, reducing the effective drug concentration at the target site.

38. Porin channel(膜孔蛋白通道)
Bacterial Resistance
Mechanism of bacterial resistance
Porin channel(膜孔蛋白通道)

39. Mechanism of bacterial resistance
④ Target alteration :
Mutation of the natural target(such as resistance to fluoroquinolone).
Target modification(ribosomal protection type of resistance to macrolides and tetracyclines).
Substitution with a resistant alternative to the natural, susceptible target (such as methicillin resistance in staphylococci).

40. ③Transformation(转化); ④Conjugation(接合).
Bacterial Resistance
The transfer of resistance genes:
①Mutations(突变);
②Transduction(转导);
③Transformation(转化);
④Conjugation(接合).

41. The transfer of resistance genes
Bacterial Resistance
The transfer of resistance genes
①Mutations(突变):
which may occur in the gene encoding.
1)The target protein;
2)The protein involved in drug transport;
3)Act on regulatory gene or promoter(启动子) affecting expression of the target, a transport protein, or an inactivating enzyme.
such as aminoglycosides, quinolones, etc.

42. The transfer of resistance genes
Bacterial Resistance
The transfer of resistance genes

43. Mutations May occur in the gene encoding i) The target protein
ii) A protein involved in drug transport
iii) A protein important for drug activation
iv) A regulatory gene or promoter
affecting expression of the target, a
transport protein, or an inactivating
enzyme.

44. The transfer of resistance genes
Bacterial Resistance
The transfer of resistance genes
②Transduction(转导):
acquisition of bacterial DNA from bacteriophage(噬菌体) that has incorporated DNA from a previous host bacterium within its outer protein coat.
Some phages can carry plasmids that code for penicillinase, or genes encod-ing resistance to erythromycin, tetracy-cline, or chioramphenicol.

45. Transduction
Transduction is acquisition of bacterial DNA from a bacteriophage (噬菌体）that has incorporated DNA from a previous host bacterium within its outer protein coat. Some phages can carry plasmids that code for penicillinase, or genes encoding resistance to erythromycin, tetracycline, or chloramphenicol.

46. The transfer of resistance genes
Bacterial Resistance
The transfer of resistance genes
③Transformation(转化):
Uptake and incorporation of DNA that is free in the environment into the host genome by homologous recombination.

47. The transfer of resistance genes
Bacterial Resistance
The transfer of resistance genes

48. The transfer of resistance genes
Bacterial Resistance
The transfer of resistance genes
④Conjugation(接合):
The passage of genes from cell to cell by direct contact through a sex pilus(性菌毛) or bridge(桥接).

49. Transformation Conjugation Bacterial Resistance
Transformation Uptake and incorporation of DNA that is free in the environment into the host genome by homolgous recombination.
Conjugation
The passage of genes from cell to cell by direct contact through a sex pilus or bridge is termed conjugation.

51. Multi-drug resistance MDR (了解)
耐甲氧西林金葡菌MRSA
社区获得性耐甲氧西林金葡菌（community-associated。CA—MRSA）
医院获得性耐甲氧西林金葡菌（ Hospital-associated ，HA-MRSA
Methicillin-resistant coagulase negative staphylococci, MRCNS
PBP-2a
3.Penicillin-resistant streptococcus pneumoniae, PRSP
PBP-1a, PBP-2a, PBP-2x, PBP-2b
Active efflux system
4.Vancomycin-resistant Enterococcus, VRE
van-A, van-B, van C-1, van C-2, van C-3, van D, van E

52. Multi-drug resistance MDR (略)
5. The 3rd generation-cephalosporins -resistant
Extended spectrumβ-lactamases, ESBL
Class I chromosone mediated β-lactamases
6.Carbapenem -resistant
OprD porin
7.Quinolone-resistant escherichia coli, AREC
Active efflux system

53. Let’s take a rest !