Antimicrobial Chemotherapy

1. Dr.Oruba Lec.7 Antimicrobial Chemotherapy

2. Introduction Drugs have been used for the treatment of infectious diseases since the 17th century (eg, quinine for malaria, emetine for amebiasis); however, chemotherapy as a science began in the first decade of the 20th century with understanding of the principles of selective toxicity, the specific chemical relationships between microbial pathogens and drugs, the development of drug resistance, and the role of combined therapy. Experiments led to the arsphenamines for syphilis, the first planned chemotherapeutic regimen.

3. Definitions • Chemotherapy The use of drugs to treat a disease • Antimicrobial drugs Interfere with the growth of microbes within a host • Antibiotic Substance produced by a microbe that, in small amounts, inhibits another microbe • Selective toxicity A drug that kills harmful microbes without damaging the host • Bacteriostatic/ Modes of action that either kill or bacteriocidal inhibit growth • Spectrum of activity Range of effect within or between groups of microbes; narrow vs.broad-spectrum

4. In 1928 Sir Alexander Fleming accidentally stumbled upon the discovery of the wonder drug, penicillin. As he was inspecting a plate of Staphylococcus aureuscontaminated with the mold Penicillium,

5. bb 1-Synthetic drugs (agents):- They synthesized chemically. For example (sulfonamides, Imidasoles, Metronidazoles, flucytion, ethambutol, Isoniazid, Nalidixic acid, Nitrofurantion). 2-Natural products (antibiotics):- These substance of microbial origin, i.e., synthesized by the microb; and have antimicrobial action, So these antibiotic produced by fungi or bacteria or even plants animals such as algae. Type of Antimicrobial Chemotherapeutic Agents drugs:- -Examples of antibiotic from fungi are Penicillin's and cephalosparins. -Examples of antibiotic from bacteria are Bacitracin and Polymyxins. -Examples of antibiotic from streptomyces species are Tetracyclin, Choloramphenicol, erythromycin, Streptomycin, Vancomycin, Kanamycin, lincomycin, Cycloserine and Polyenes….etc.

6. Semi synthetic Antibiotics:- Is result from modification of natural products such as derivative of penicillin and cephalosporin. Selective Toxicity:- Selective toxicity may be a function of a specific receptor required for drug attachment, or it may depend on the inhibition of biochemical events essential to the pathogen but not to the host. *Each antibiotic has either broad or narrow spectrum.

7. The broodspectrum antibiotic is active against wide rang of bacteria, e.g., G+ve and G-ve bacteria. The narrawspectrum antibiotic is active against few organisms. The mechanism of action of antimicrobial drugs:- The mechanisms of action of antimicrobial drugs can be discussed under four headings: I. Inhibition of cell wall synthesis. II. Inhibition of cell membrane function, e.g., alteration of cell membrane permeability or inhibition of active transcription. III. Inhibition of protein synthesis, i.e., inhibit translation and transcription. IV. Inhibition of nucleic acid synthesis.

8. Classification of antimicrobial drugs according to their mode of action ''site of action'':- Ι.Drugs that inhibit cell wall synthesis ''Peptidoglycan synthesis'':- They act by damaging the plasma membrane, i.e., inhibit early steps in the biosynthesis of peptidoglycan. 1-Penicillins 2-Cephalosporinscell wall synthesis ''Peptidoglycan synthesis'':- 3-Bactracin 4-Vancomycin 5-Ristocetin They act by blocking the peptidoglycan by inhibition of transpeptidation, i.e., blocking the cross linking of peptidoglycan. 6-Novobiocin 7-Cycloserine:- It act by inhibition of incorporation of D-alanine into peptidoglycan of bacterial cell wall by blocking alanine racemase enzyme.

9. *Cycloserine act as analoge to D-alanine. The difference is susceptibility of G+ve and G-ve bacteria to penicillins or cephalosporins depends or structural difference in their cell wall a-amount of peptidoglycan b-Presence of receptors c-lipid nature of cross linking d-activity of autolytic enzymes. II. Drugs that inhibit cell membrane function:- 1-Polymyxins:- It act by binding to membrane rich in phosotidyl ethanolamine leading to disruption of cell membrane. (This action is similar to that cationic detergents). 2-Polyene Antibiotics (A , Amphotericin B, Nystatin):- The act by binding to membrane sterol. 3-Imidazoles:- They act by preventing the biosynthesis of the membrane lipid.

10. III. Drugs that inhibit protien synthesis:- 1-Aminoglycoside antibiotics 2-Tetracyclines antibiotics. 3-Spectinomycin antibiotics. They act by binding to the 30s subunit of bacterial ribosome's. *The aminglycosides include gentamicin, neomycin, kanamycin, streptomycin, tobramycin, netilmycin, and amikacin. They act by binding to 50s subunit of bacterial ribosomes. 4-Macrolides (erythromycin, oleandomycin) 5-Lincomycin and clindamycin.

11. IV. Drugs that inhibit nucleic acid synthesis:- A – drugs that inhibit DNA synthesis:- *1- Actinomycin:- it act by formation of complex with DNA. *2- Mitomycin:- it act by blocking DNA replication. 3- Sulfonamides:- they act by inhibition of the formation of folic acid from P-amino benzoic acid(PABA) by competition with PABA,i.e., inhibition of folate metabolism. 4-Trimethoprim:- it act by inhibition of dihydrofolate reductase. * 5- Isoniazid:- act by compete with pyridoxine. *Isoniazid = Iso nicotinic acid hydrazid (INH). * Actinomycin and Mitomycin are not used for treatment of infection , but inhibit bacterial and animal cells.

12. 6-Quinolones (Nalidixic acid, oxolinic acid):- They act by blocking DNA gyrase (Topoisomerase II  ) Inhibition of DNA synthesis B. Drugs inhibit RNA synthesis:- *Rifampicin:- It inhibits RNA synthesis by blocking the RNA polymerase.

13. Summary of Targets

15. References: • 1- Jawetz, Melnick, & Adelberg’s.( 2013). Medical Microbiology (Twenty-Sixth Edition). • 2- Kenneth Todar. (2008).Todar’s Online Textbook of Bacteriology ,University of Wisconsin.

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