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

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

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

Section 1 General Concept of Antimicrobial Drugs

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

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

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

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

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

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

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

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

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

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

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

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

Section 2 Mechanism of Antimicrobial Action

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

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

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

cytoplasm plasma membrane cell wall Vancomycin -Lactam

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

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

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

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

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

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

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

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

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:

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

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

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

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

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

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

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

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

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

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

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