Antimicrobial Drugs

1. Antimicrobial Drugs

2. Antimicrobial Drugs • Chemicals used to treat microbial infections • Before antimicrobials, large number of people died from common illnesses • Now many illnesses easily treated with antimicrobials • However, many antimicrobial drugs are becoming less useful

3. Antimicrobial Drugs • Chemotherapeutic agent= • Antimicrobial drug= • Different types of antimicrobial drugs: • Antibacterial drugs • Antifungal drugs • Antiprotozoan drugs • Antihelminthic drugs

5. Paul Ehrlich • He observed that certain dyes stain bacterial cells and not animal cells • Theorized that there could be a dye or chemical that would harm bacterial cells but not human cells • Systematic search for chemical to cure syphilis • 606th compound tested proved to be highly effective in treating laboratory animals

6. Gerhard Domagk • Discovered red dye, Prontosil effective in treating Streococcal infections in animals • No effect in test tubes • Enzymes in animals blood split Prontosil molecule into sulfanilamide- this acted against streptococcal • Sulfa Drug

7. Alexander Fleming • Working on cultures of Staphylococcus • Contamination with mold • Noticed colonies growing near mold looked odd • Found that mold was secreting substance that was killing bacteria

8. Figure 20.1

9. Features of Antimicrobial Drugs • Most modern antibiotics come from species of microorganisms that live in the soil • To commercially produce antibiotic: • Select strain and grow in broth • When maximum antibiotic concentration reached, extract from medium • Purify • Chemical alter to make it more stable

10. Features of Antimicrobial Drugs:Selective Toxicity • Cause greater harm to microorganisms than to host • Chemotherapeutic index= lowest dose toxic to patient divided by dose typically used for therapy

11. Features of Antimicrobial Drugs: Antimicrobial Action • Bacteriostatic: inhibit growth of microorganisms • Bactericidal: Kill microorganisms

12. Features of Antimicrobial Drugs:Spectrum of Activity • Antimicrobial medications vary with respect to the range of microorganisms they kill or inhibit • Some kill only limited range : Narrow-spectrum antimicrobial • While others kill wide range of microorganisms: Broad-spectrum antimicrobial

14. Features of Antimicrobial Drugs:Effects of Combining Drugs • Combinations are sometimes used to fight infections • Synergistic: action of one drug enhances the activity of another • Antagonistic: activity of one drug interferes with the action of another

15. Features of Antimicrobial Drugs:Adverse Effects • Allergic Reactions: some people develop hypersensitivities to antimicrobials • Toxic Effects: some antimicrobials toxic at high concentrations or cause adverse effects • Suppression of normal flora: when normal flora killed, other pathogens may be able to grow to high numbers

16. Features of Antimicrobial Drugs:Resistance to Antimicrobials • Some microorganisms inherently resistant to effects of a particular drug • Other previously sensitive microorganisms can develop resistance through spontaneous mutations or acquisition of new genes

17. Mechanisms of action of Antibacterial Drugs • Inhibit cell wall synthesis • Inhibit protein synthesis • Inhibit nucleic acid synthesis • Injury to plasma membrane • Inhibit synthesis of essential metabolites

18. Figure 20.2

19. b-Lactam Drugs- inhibit cell wall synthesis • Irreversibly inhibit enzymes involved in the final steps of cell wall synthesis • These enzymes mediate formation of peptide bridges between adjacent stands of peptidoglycan • b-lactam ring similar in structure to normal substrate of enzyme • Drug binds to enzyme, competitively inhibit enzymatic activity

21. b-Lactam Drugs • Some bacteria produce b-lactamase- enzyme that breaks the critical b-lactam ring • b-lactam drugs include: penicillins and cephalosporins

22. Antibacterial medications that inhibit protein synthesis • Target ribosomes of bacteria • Aminoglycosides: bind to 30S subunit causing it to distort and malfunction; blocks initiation of translation • Tetracyclines: bind to 30S subunit blocking attachment of tRNA • Macrolides: bind 50S subunit and prevents continuation of protein synthesis

23. Figure 20.4b

24. Antibacterial medications that inhibit nucleic acid synthesis • Target enzymes required for nucleic acid synthesis • Fluoroquinolones: inhibit enzymes that maintain the supercoiling of closed circular DNA • Rifamycins: block prokaryotic RNA polymerase from initiating transcription

25. Antibacterial medications injure plasma membrane • Polymyxin B: binds to membrane of G- bacteria and alters permeability • This leads to leakage of cellular contents and cell death • These drugs also bind to eukaryotic cells to some extent, which limits their use to topical applications

26. Antibacterial drugs that inhibit synthesis of essential metabolites • Competitive inhibition by substance that resembles normal substrate of enzyme • Sulfa drugs

27. Antiviral Drugs • Very few antiviral drugs approved for use in US • Effective against a very limited group of diseases • Targets for antiviral drugs are various points of viral reproduction

28. Nucleoside and Nucleotide analogs • Acyclovir- used to treat genital herpes • Cidofovir- used for treatment of cytomegaloviral infections of the eye • Lamivudine- used to treat Hepatitus B

31. Antiretrovirals • Currently implies, a drug used to treat HIV • Tenofovir- nucleotide reverse transcriptase inhibitor • Zidovudine- nucleoside analog

32. Other enzyme inhibitors • Zanamivir (Relenza) and Oseltamivir phosphate (Tamiflu)- inhibitors of the enzyme neuominidase • Used to treat influenza • Indinavir- protease inhibitors

33. Interferons • Cells infected by a virus often produce interferon, which inhibits further spread of the infection • Alpha-interferon- drug for treatment of viral hepatitis infections

34. Antifungal drugs • More difficult to find point of selective toxicity in eukaryotes than in prokaryotes • Targets of antifungal drugs: • Agents affecting fungal sterols • Agents affecting fungal cell walls • Agents inhibiting nucleic acids

35. Agents affecting fungal sterols • Many antifungals target the sterols in the plasma membrane • Polyenes- used in systemic fungal infections, very toxic to kidneys • Azoles- used for athlete’s foot and vaginal yeast infections (miconizole)

36. Agents affecting fungal cell walls • primary target of selective toxicity is β-glucan • Inhibition of synthesis of this glucan results in an incomplete cell wall, and results in lysis of the cell • Caspofungin- first new class of antifungals in 40 years

37. Agents inhibiting nucleic acids • Flucytin- nucleotide analog of cytosine, interferes with the biosynthesis of RNA, and therefore protein synthesis

38. Antiprotozoan drugs • Quinine still used to control malaria • Chloroquinone- synthetic derivative has largely replaced it • Mefloquinone- used in areas where resistance to chloroquinone has developed • Quinacrine- drug of choice for treating protozoan disease, giardiasis

39. Antihelminthic drugs • Praziquantel- used in treatment of tapeworms; kills worms by altering permeability of plasma membranes

40. Kirby-Bauer method for determining drug susceptibility • Bacteria spread on surface of agar plate • 12 disks, each with different antimicrobial drug, placed on agar plate • Incubated- drugs diffuse outward and kill susceptible bacteria • Zone of inhibition around each disk • Compare size of zone to chart

41. Figure 21.10

42. Resistance to antimicrobial drugs • Drug resistance limits use of ALL known antimicrobials • Penicillin G: first introduced, only 3% of bacteria resistant • Now, over 90% are resistant

44. How do bacteria become resistant? • Spontaneous Mutation: happen as cells replicate • Gene Transfer: Usually spread through conjugative transfer of R plasmid

45. Slowing the emergence and spread of antimicrobial resistance • Responsibilities of Physicians: must work to identify microbe and prescribe suitable antimicrobials, must educate patients • Responsibilities of Patients: need to carefully follow instructions

46. Slowing the emergence and spread of antimicrobial resistance 3.Educate Public: must understand appropriateness and limitations of antibiotics; antibiotics not effective against viruses 4.Global Impacts: organism that is resistant can quickly travel to another country - in some countries antibiotics available on non-prescription basis - antibiotics fed to animals can select for drug- resistant organisms

48. New Approaches to Antibiotic Therapy Are Needed • Scientists work to find new antibiotic targets in pathogens • Discovery of new and unique antibiotics is necessary