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The Evolution of Antimicrobial Drugs: From Paul Ehrlich to Modern Antibiotics

Explore the history and development of antimicrobial drugs, starting with Paul Ehrlich's quest for the "magic bullet" in 1910, leading to the discovery of antibiotics by Alexander Fleming in 1928. This overview covers key milestones in antibiotic development, including the work on penicillin, cephalosporins, and other antimicrobial agents, showcasing their mechanisms of action against various microbes. Delve into the challenges of antibiotic resistance and the methods used to test microbial sensitivity, highlighting the ongoing battle in the field of infectious diseases.

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The Evolution of Antimicrobial Drugs: From Paul Ehrlich to Modern Antibiotics

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  1. Antimicrobial Drugs

  2. The dawn of antibiotics • Paul Erlich (1910) • Wanted to find the “magic bullet” for syphilis • proposed the idea of the blood brain barrier • Worked at staining tissues and first to come up with the idea behind “selective toxicity” • Nobel Prize in 1908

  3. Alexander Fleming • A physician who studied bacterial action of blood and antisepsis • Discovered and named Lysozyme • Discovered mold growing on an agan plate(1928) • 1945 Nobel Prize in Physiology or Medicine along with Chain and Florey

  4. Chain and Florey • 1940 developed a system for growing Penicillium and purifying the drug • Tested the drug in mice, passed all trials • Received the Nobel Prize in 1945 with Alexander Fleming for their work

  5. Antibiotics • A substance produced by a microorganism that inhibits or kills other microbes

  6. Microbes that produce antibiotics

  7. Range of activity • Narrow range: target one group of microbes • Broad range: target a wide group of different microbes • Which one is the best?

  8. Spectrum of activity

  9. Targets of antimicrobial drugs

  10. Targets of Cell Wall Synthesis

  11. How does penicillin work? • Inhibits formation of tetrapeptide side chains….which means…. • What happens if you put a cell in a solution with penicillin?

  12. Some drugs target protein synthesis

  13. Penicillin weakens the cell wall

  14. Beta-lactam ring common with penicillins and cephalosporins

  15. How organisms degrade penicillins

  16. Family of Penicillins • Natural penicillins- • Penicillin G and V • Penicillinase-resistant penicillins • Methicillin, Dicloxacillin • Broad-spectrum penicillins • Ampicillin, Amoxicillin • Extended-spectrum penicillins • Ticaricillin, Piperacillin • Penicillins plus beta-lactamase inhibitors • Augmentin (amoxicillin and clavulanic acid)

  17. Side chain varies for derivatives of penicillin

  18. Cephalosporins • Derived from fungus, Acremonium cephalosporium • Chemical structure makes them resistant to beta-lactamase, low affinity for penicillin binding proteins • Grouped into first, second, third, and fourth generation cephalosporins

  19. Vancomycin • Binds to the terminal amino acids of the peptide chain of NAM molecules, blocks peptidoglycan formation

  20. Antibiotics that inhibit protein synthesis

  21. Aminoglycosides • Bactericidal • Irreversibly bind to 30S ribosome, cause misreading of the mRNA • Transported into cells that actively respire (not effective against ananerobes, streptococci, enterococci) • Ex: streptomycin, gentamicin, tobramycin

  22. Tetracyclines • Bind reversibly to 30S, block attachment of the tRNA to ribosome • Actively transported into bacterial cells • Effective against gram positive and gram negative • Resistance: due to decrease in uptake or increase in excretion • Ex: Doxycycline

  23. Macrolides • Reversibly bind to the 50S, prevent continuation of protein synthesis • Drug of choice for patients allergic to penicillins • Not good for Enterobacteriaceae • Ex: Erythromycin, Azithromycin • Resistance: enzymes that alter drug, decreased uptake

  24. Oxazolidinones • Reversibly bind to the 50S subunit, interfere with initiation of protein synthesis • Used for treating gram positive infections resistant to Beta-lactam drugs and Vancomycin • Ex: Linezolid

  25. Antibiotics that inhibit nucleic acid synthesis • Fluoroquinolones • Inhibit topoisomerase • Rifamycins • Blocks prokaryotic RNA polymerase from initiating transcription

  26. Antibiotics that inhibit metabolic pathways • Sulfonamides • Trimethoprims

  27. Sulfonamides (sulfa drugs) • First synthetic drugs to treat microbial infections • Used to treat urinary tract infections (UTIs) • Combination of trimethoprim and sulfamethoxazole (TMP-SMZ) example of synergism

  28. Tests for microbial sensitivity • Kirby-Bauer (disk diffusion method) • We did this in lab • Determining the Minimum Inhibitory Concentration (MIC) • E test • easier way to determine the MIC

  29. Kirby-Bauer tests for sensitivity

  30. Determining the Minimum Inhibitory Concentration (MIC)

  31. E-test for MIC

  32. What resistance looks like…

  33. Mechanisms of Drug resistance • Destruction or inactivation of the drug • Prevention of penetration to target site • Alteration of target site (mutation) • Pumping of the drug out of the bacterial cell

  34. Emerging Antibiotic Resistance • Enterococci • Staphylococcus aureus • Steptococcus pneumoniae • Mycobacterium tuberculosis

  35. Targets of Viral drugs

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