1. Chemotherapeutic Medicine
Li Chen
Department of Pharmacology
School of Basic Medical Science
Jilin University

2. Classification Antibacterial drugs(35-40) Antifungal drugs(41)
Antiviral drugs
Antimicrobial agents
Antiparasitic agents (44)
Anticancer drug (45)

3. Antimicrobial Agents: General Consideration
General concept
Mechanism of action
Bacterial Resistance

4. Section 1
General Concept of Antimicrobial Drugs

5. Antibacterial drugs
The drugs that inhibit or kill the bacterial, including antibiotics and artificial drugs

6. Antibiotics
The agents which are produced by microbes, could inhibit or kill other microbes growth and finally destroy them.

7. Antibacterial spectrum
The antibacterial range of the anti-bacterial drugs
broad-spectrum antibacterial drugs
narrow-spectrum antibacterial drugs

8. Broad-spectrum antibacterial drugs
affect a wide variety of microbial species
tetracycline, chloramphenicol, fluoroquinolones

9. Narrow-spectrum antibacterial drugs
act only on a single or a limited groups of microorganisms
isoniazid

10. Antibacterial activity
Antibacterial drug’s competence of inhibiting and killing bacterium

11. Bacteriostatic drugs
Drugs that inhibit the growth of the bacteria without causing cell death
tetracyclines, macrolides, clindamycin, chloramphenicol and sulfonamides

12. β-lactams, Vancomycin, aminoglycosides and fluoroquinolones.
Bactericidal drugs
Drugs that kill bacteria
β-lactams, Vancomycin, aminoglycosides and fluoroquinolones.

13. Minimal inhibitory concentration, MIC
The lowest concentration of drug that inhibits growth of the microbes

14. Minimal bactericidal concentration, MBC
The lowest concentration of drug that kill microbes

15. Chemotherapeutic index
The ratio of the toxic dose to the therapeutic dose of chemotherapeutic medicines

16. Post-antibiotic effect, PAE
Antibacterial activity persists beyond the time that measurable drug is present

17. Section 2
Mechanism of Antimicrobial Action

18. cell wall synthesis
plasma membrane integrity
Protein synthesis
nucleotide synthesis
folate synthesis.

19. 1. Inhibition synthesis of bacterial cell wall
Function：
1). Maintain Bacterial shape
2). Barrier function
3). permeation

20. Cell wall: peptidoglycan
N-acetylated muramic acid(NAM)
N-acetylated glucosamine(NAG)

21. cytoplasm plasma membrane cell wall
Vancomycin
-Lactam

22. 2. Increased permeability of cytoplasmic membranes
Bacterium
lipid (phospholipid, glucolipid)
protein
polysaccharide (peptidoglycan)
Fungi
ergosterol
Principles of pharmacology, chapter 36 page 581
Basic & Clinical Pharmacology chapter 50 page 846
The pharmacological basis of therapeutics Section VIII chemotherapy of microbial disease, chapter 47 page 1262

23. 1). Polymyxins: interact with phospholipid 2). Antifungal agents:
Polyenes bind to ergosterol
Azoles block ergosterol biosynthesis
Principles of pharmacology, chapter 36 page 581
Basic & Clinical Pharmacology chapter 50 page 846
The pharmacological basis of therapeutics Section VIII chemotherapy of microbial disease, chapter 47 page 1262

24. 3. Inhibition of protein biosynthesis
Ribosome
Big subunit
Small subunit
Bacterium
70S
50S
23S, 5S rRNA
31 proteins
30S
16S rRNA
21 proteins
Mammalian
80S
60S
28S, 5S rRNA
49proteins
40S
33proteins

25. Protein Biosynthesis Tetracyclines (30S) Aminoglycosides (30S)
Decoding
Tetracyclines
(30S) P A
Aminoglycosides
(30S)
Aminoglycosides
(30S)
Chloramphenicol
Lincomycin (50S)
Peptidyl transferase
Macrolides(50S) P A P A
Translocase

26. 4. Interference with nucleotide synthesis
1). DNA uncoiling：helicase
2). primosome and primer：primase
3). DNA replication：
DNA polymerase
DNA gyrase
DNA ligase

27. Rifampin: inhibit DNA-directed RNA
polymerase
Quinolones: inhibit DNA gyrase, and DNA Replication

28. 5. Inhibition of the folate metabolism
PABA + Pteridine
Dihydropteroate
synthase
Sulfonamides
Dihydropteroic acid
Glutamate
Dihydrofolate
Trimethoprim
(TMP)
Dihydrofolate
reductase(DHFR)
Principle of pharmocology chapter 31 page 511 fig. 31-6
Tetrahydrofolate
Purine、
pyrimidine nucleotide
precursor

29. Mechanism of action Polymyxin Polyenes Azoles -lactam Vancomycin
DNA
Plasma membrane
Cell wall
PABA
DHF A
THF A
50S
30S
Quinolones
mRNA
TMP
Sulfonamides
Rifampin
Tetracyclines
Aminoglycosides Macrolides Chloramphenicol
Lincomycin

30. Section 3 Bacterial Resistance
1. Classification of bacterial resistance
Intrinsic resistance
Acquired resistance
Gram-negative organisms
Vancomycin
Pseudomonas aeruginosa
Ampicillin
Intrinsic resistance:
chromosomal mutation usually occur in the genes , these mutations can then be conferred on daughter cells(vertical transmission), bacteria also can acquire resistance by gaining genetic material from other vacteria (horizontal transmission)), transmited to future generations.(chapter 30 principles of chemotherapy page 501, principles of pharmacology)
2.acquires resistance:

31. 2. Mechanisms of Resistance
Production of enzymes that inactivate the drug
Modification of target sites
Decrease the permeability of cell membrane
Active drug efflux from the cell

32. 1) Production of enzymes that inactivate the drug
β-Lactamase :
Penicilline resistance: penicillinase
Cephalosporins resistance：
super broad spectrum β-Lactamase （ESBLs）
Lactamase inhibitor resistance:
AmpC type enzyme

33. Non β-Lactamase ：
Chloramphenicols: acetyltransferase
nucleoside transferase
Aminoglycosides: phosphotransferase
acetyltransferase
Macrolides: acetyltransferase

34. Methylation of an adenine of the 23S bacterial ribosomal RNA
2) Modification of target sites
Macrolide
Methylation of an adenine of the 23S bacterial ribosomal RNA
Modify target protein binding site
(2) Produce new target protein
Methicillin resistance in staphylococci
penicillin resistance in pneumococci and enterococci
New PBPs

35. 3) Decrease the permeability of cell
OmpF
-lactam, Tetracyclines, Quinolones, Chloramphenicol
3) Decrease the permeability of cell
out membrane
4) Increased active efflux system

36. Drug efflux system Efflux transporter ： Accessory protein ：
outer membrane protein：

38. Increased active efflux system
-lactam, Tetracyclines, Quinolones, Chloramphenicol, Macrolides,

39. 3. Transference mode of drug resistance gene
Quinolones
Mutation
Transduction
Transformation
Conjugation
Tetracycline
Penicillin
Vancomycin

40. 4. Multi-drug resistance
Methicillin -resistant staphylococcus aureus
Penicillin-resistant streptococcus pneumoniae
Vancomycin-resistant enterococcus

41. Third –generation cephalosporins-resistance gram negative bacilli
carbapenem -resistance Pseudomonas aeruginosa
Quinolone-resistance escherichia coli

42. Classification of antibacterial drugs
β –Lactam
Macrolides
Lincosamides
polypeptides
aminoglycosides
Tetracyclines
Choramphenicols
Other Antibiotics
Antibiotics
Synthesis antibacterial drugs
quinolones
Sulfonamides