Drugs, Microbes, Host – The Elements of Chemotherapy

1. Drugs, Microbes, Host – The Elements of Chemotherapy Chapter 13

2. History of Microbiology Chemotherapy – treatment with chemicals • 1910: Paul Ehrlich developed a synthetic arsenic drug, salvarsan, to treat syphilis. • 1922: Alexander Fleming discovered lysozyme in tears, saliva and sweat. Lysozyme was the first body secretion shown to have chemotherapeutic properties! • 1930s: Sulfonamides were synthesized and are still used!

3. History of Microbiology 1928: Alexander Fleming discovered the first antibiotic. • He observed that Penicillium fungus made an antibiotic, penicillin, that killed S. aureus. • 1940s: Penicillin was tested clinically and mass produced.

5. Survey of Major Antimicrobial Drug Groups Antibacterial drugs Antibiotics Synthetic drugs Antifungal drugs Antiparasitic drugs Antiviral drugs About 260 different antimicrobial drugs are classified in 20 drug families.

6. Origins of Antimicrobial Drugs • Antibiotics are common metabolic products of aerobic spore-forming bacteria & fungi. • bacteria in genera Streptomyces & Bacillus • molds in genera Penicillium & Cephalosporium • By inhibiting the other microbes in the same habitat, antibiotic producers have less competition for nutrients & space.

7. The Spectrum of Antibiotic Activity

8. Selectively Toxic • Drugs should kill or inhibit microbial cells without simultaneously damaging host tissues. • As the characteristics of the infectious agent become more similar to the vertebrate host cell, complete selective toxicity becomes more difficult to achieve & more side effects are seen. Take advantage of any cellular/molecular differences between host (patient) and microbe!

9. Targets of Antimicrobial Drugs • Inhibition of cell wall synthesis • Disruption of cell membrane structure or function • Inhibition of protein synthesis • Inhibition of nucleic acid synthesis, structure or function • Block metabolic reactions

10. Know this!!!

11. 1. Drugs that Affect the Bacterial Cell Wall Most bacterial cell walls contain a rigid girdle of peptidoglycan. Penicillin and cephalosporin block synthesis of peptidoglycan, causing the cell wall to lyse. Penicillins do not penetrate the outer membrane and are less effective against gram-negative bacteria. Broad spectrum penicillins and cephalosporins can cross the outer membranes of gram-negative bacteria.

12. Penicillins Large diverse group of compounds Can synthesized in the laboratory More economical to obtain natural penicillin through microbial fermentation and modify it to semi-synthetic forms Penicilliumchrysogenum – major source All penicillins consist of 3 parts thiazolidine ring beta-lactam ring variable side chain dictates microbial activity

13. Chemical Structure of Penicillins The R group is responsible for the activity of the drug, and cleavage of the beta-lactam ring will render the drug inactive. Penicillinase (β-lactamase)

14. Semisynthetic Penicillins • Penicilinase-resistant penicillins • Carbapenems: very broad spectrum • Monobactam: Gram negative • Extended-spectrum penicillins • Penicillins + -lactamase inhibitors • Primary problems – allergies and resistant strains of bacteria

15. Cephalosporins Account for majority of all antibiotics administered Isolated from Cephalosporium acremonium mold Beta-lactam ring that can be altered Relatively broad-spectrum, resistant to most penicillinases, & cause fewer allergic reactions • 2nd, 3rd, and 4th generations more effective against gram-negatives

16. Know this!!!

17. Other Inhibitors of Cell Wall Synthesis • Bacitracin • Topical application • Against gram-positives • Vancomycin • Glycopeptide • Important "last line" against antibiotic resistant S. aureus

18. 2. Drugs That Disrupt Cell Membrane Function A cell with a damaged membrane dies from a disruption in metabolism or lysis. These drugs have specificity for a particular microbial group, based on differences in types of lipids in their cell membranes. Polymyxins interact with phospholipids and cause leakage, particularly in gram-negative bacteria • Polymyxin B (Gram negatives) • Topical • Combined with bacitracin and neomycin (broad spectrum) in over-the-counter preparation

19. Targets of Antimicrobial Drugs • Inhibition of cell wall synthesis • Disruption of cell membrane structure or function • Inhibition of protein synthesis • Inhibition of nucleic acid synthesis, structure or function • Block metabolic reactions

20. Ribosomes of eukaryotes differ in size and structure from prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria. Streptomycin inserts on sites on the 30S subunit and cause misreading of mRNA. Tetracyclines block attachment of tRNA on the A acceptor site and stop further synthesis. 50S 30S 3. Drugs That Block Protein Synthesis

21. Protein Synthesis Inhibitors Tetracycline Antibiotics • Broad-spectrum, block protein synthesis (blocks attachment of tRNA) • Low cost • Doxycycline & minocycline – oral drugs taken for STDs, Rocky Mountain spotted fever, Lyme disease, typhus, acne & protozoa

22. 3. Drugs That Block Protein Synthesis streptomycin 30S 30S = know these

23. Protein Synthesis Inhibitors Chloramphenicol • Isolated from Streptomyces venezuelae • Potent broad-spectrum drug with unique nitrobenzene structure • Blocks peptide bond formation • No longer derived from natural source • Very toxic, restricted uses, can cause irreversible damage to bone marrow • Typhoid fever, brain abscesses, rickettsial & chlamydial infections

24. Protein Synthesis Inhibitors Erythromycin • Also inhibits protein synthesis (attaches to bacterial ribosomes) • Broad-spectrum, (side effects: fairly low toxicity!) • Given to children • Taken orally for Mycoplasma pneumonia, legionellosis, Chlamydia, pertussis, diptheria and as a prophylactic prior to intestinal surgery • Newer semi-synthetic macrolides – clarithomycin, azithromycin

25. Know this!!!

26. 4. Inhibitors of Nucleic Acid Synthesis • Rifamycins (Rifampin) • Inhibits RNA synthesis (transcription!) • Leprosy, Tuberculosis, • Quinolones • Ciprofloxacin (cipro) • Inhibits DNA gyrase • Wide applications (including…respiratory and urinary tract infections, anthrax)

27. Targets of Antimicrobial Drugs • Inhibition of cell wall synthesis • Disruption of cell membrane structure or function • Inhibition of protein synthesis • Inhibition of nucleic acid synthesis, structure or function • Block metabolic reactions

28. 5. Drugs That Block Metabolic Reactions • Sulfonamides and trimethoprim block enzymes required for tetrahydrofolate synthesis needed for DNA & RNA synthesis. Broad spectrum! • Competitive inhibition – drug competes with normal substrate for enzyme’s active site • Synergistic effect – an additive effect, achieved by multiple drugs working together, requiring a lower dose of each

29. New Classes of Antibiotics • Fosfomycin trimethamine – a phosporic acid effective as alternate treatment for UTIs • inhibits cell wall synthesis • Synercid – effective against Staphylococcus & Enterococcus that cause endocarditis & surgical infections; • inhibits protein synthesis

30. Miscellaneous Antibacterial Drugs • Isoniazid – used with rifampicin to treat TB (primary treatment) • Inhibits mycolic acid synthesis in the mycobacterial cell wall • Oxazolidinones-new class of antibacterial drugs inhibit initiation of protein synthesis • Linezolid – MRSA (Methicillin-Resistant Staphylococcus aureus) VRE (Vancomycin-Resistant Enterococcus) • Fluoroquinolones –broad-spectrum, potent • norfloxacin, ciprofloxacin (cipro) – UTI, STD, GI, osteomyletitis, respiratory & soft tissue infections • sparofloxacin, levofloxacin – pneumonia, bronchitis, sinusitis

31. Fungi of Medical Importance • Fungal diseases are referred to as mycoses • Cutaneous mycoses (dermatophytoses) • Fungi have keratinase – degrade keratin on skin, nails and hair • Examples: ringworm, athletes foot, jock itch • Systemic mycoses • Usually caused by soil fungi • Special problems in immunocompromised hosts • Examples: pneumocystis pneumonia, valley fever

32. Disrupt plasma membrane Antifungal Drugs • Amphotericin B–mimic lipids, most versatile & effective, topical & systemic treatments • Nystatin – topical treatment • Griseofulvin – stubborn cases of dermatophyte infections (jock itch, athlete’s foot) • Flucytosine – analog of cytosine; cutaneous mycoses or in combination with amphotericin B for systemic mycoses

33. Antiparasitic Drugs • Antimalarial drugs – • Quinine, chloroquinine, primaquine, • Antiprotozoan drugs – • Metronidazole (Flagyl), quinicrine, sulfonamides, tetracyclines • Antihelminthic drugs – immobilize, disintegrate, or inhibit metabolism • Mebendazole -- broad-spectrum: • inhibit function of microtubules, interfers with glucose utilization & disables them • pyrantel, piperazine- paralyze muscles • niclosamide – destroys scolex