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Antimicrobial Drugs: Evolution & Therapeutic Uses

Explore the history and mechanisms of antimicrobial drugs, from Paul Ehrlich's Salvarsan to modern antibiotics. Learn about the action spectrum, tissue distribution, and resistance mechanisms of these crucial medications.

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Antimicrobial Drugs: Evolution & Therapeutic Uses

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  1. Ch 20 Antimicrobial Drugs

  2. Antimicrobial Drugs • Chemotherapy: The use of drugs to treat a disease. • Antimicrobial drugs: Interfere with the growth of microbes within a host. • Antibiotic: Of biological origin. Produced by a microbe, inhibits other microbes. • Chemotherapeutic agent: synthetic chemicals • Today distinction blurred  many newer "antibiotics" are biological products that are • chemically modified or • chemically synthesized

  3. Features of Antimicrobial Drugs • Selective toxicity: Drug kills pathogens without damaging the host. • Therapeutic index: ratio between toxic dose and therapeutic dose – or ratio of LD50 to ED50High therapeutic index  less toxic • Antimicrobial action – Bacteriostatic vs. bactericidal • Activity Spectrum – Broad-spectrum vs. narrow- spectrum • Tissue distribution, metabolism, and excretion – BBB; Unstable in acid; half-life duration

  4. The History of Chemotherapy • Paul Ehrlichand Sahachiro Hata developedSalvarsan (Arsphenamine) against syphilis in 1910: The concept of chemotherapy to treat microbial diseases was born. • Sulfa drugs (sulfanilamide) discovered in 1935  against gram + bacteria

  5. The History of Chemotherapy cont. 1928: Fleming discovered penicillin 1940: Howard Florey and Ernst Chain performed first clinical trials of penicillin. Fig 20.1

  6. The Sites of Activity in a Bacterial Cell for Various Antibiotics Compare to Fig 20.2

  7. Antibacterial AntibioticsInhibitors of Cell Wall Synthesis: Penicillin Natural and semisynthetic penicilins contain β-lactam ring Natural penicillins produced by Penicillium are effective against Gram + cocci and spirochetes Semisynthetic penicillins: made in laboratory by adding different side chains onto β-lactam ring  penicillinase resistant and broader spectrum of activity Penicillinase (β-lactamase): bacterial enzyme that destroys natural penicillins Penicillinase resistantpenicillins: methicilin replaced by oxacilin and nafcilin due to MRSA Extended-spectrum penicilins: Ampicilin, amoxicilin; new: carboxypenicilins and ureidopenicillins (also good against P. aeruginosa)

  8. Compare to Fig 20.8

  9. Cephalosporins Fungi of genus Cephalosporium  4 Generations of cephalosporins Chemical structure and mode of action resembles penicilins Advantages: More stable than penicilins to bacterial -lactamases, broader spectrum  used against penicillin-resistant strains. Incidence of cross-sensitivity with penicillin estimated at  5-16%

  10. Vancomycin • Glycopeptide from Streptomyces • Inhibition of cell wall synthesis • Used to kill MRSA • Emerging Vancomycin resistance: VRE and VRSA

  11. Antifungal Drugs • Polyenes, such as nystatin and amphotericin B, for systemic fungal infections. Combine with fungal plasma membrane sterols  fungicidal. Nephrotoxic • Griseofulvin from Penicillium. Systemic/oral. Interferes with eukaryotic cell division and is used primarily for superficial dermatophytoses.

  12. Antiviral Drugs Nucleoside analogs inhibit DNA synthesis • Acyclovir and newer derivatives: Selective inhibition of herpes virus replication. Acyclovir conversion to nucleotide analog only in virus infected cells  very little harm to uninfected cells! • AZT: reverse transcriptase inhibitor • Inhibitors of viral enzymes are used to treat influenza and HIV infection, e.g.: Protease inhibitors • -interferons inhibit spread of viruses to new cells Figure 20.16a

  13. Protease Inhibitors HIV protease cleaves viral polypeptide into functional proteins Protease inhibition  HIV cannot mature and noninfectious viruses are produced.

  14. Antiprotozoan and Antihelminthic Drugs • Chloroquine, quinacrine, diiodohydroxyquin, pentamidine, and metronidazole (Flagyl) are used to treat protozoan infections. • Antihelminthic drugs include mebendazole, praziquantel, and ivermectin.

  15. Antibiotic Assays to Guide Chemotherapy Two general methods for Susceptibility Testing: • Tube dilution method determines minimum inhibitory concentration (MIC) MIC = the lowest concentration of antibiotic sufficient to inhibit bacterial growth when tested in vitro. 2.Agar disk diffusion method determines susceptibility of an organism to a series of antibiotics. Kirby-Bauer test

  16. Drug Resistance Penicillin G resistance of S. aureus from 3% to > 90% Multidrug-resistant S. aureus = MRSA or “super-bug” Vancomycin-resistance  Multi drug resistant TB = MDR-TB Mechanisms of resistance: • Vertical evolution due to spontaneous mutation • Horizontal evolution due to gene transfer

  17. Read Microbiology In the NewsAntibiotics in Animal Feed Linked to Human Disease (p. 606) the end

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