Chapter 10 Controlling microbial growth in the body: Antimicrobials

1. Chapter 10 Controlling microbial growth in the body: Antimicrobials

2. Like disinfectants antimicrobial drugs act by killing or inhibiting the growth of microorganisms. • Antimicrobial drugs must act within the body and show _______________________.

3. Antimicrobial Drugs • Chemotherapy: the use of drugs to treat a disease • Antimicrobial drugs: interfere with the growth of microbes within a host • Selective toxicity: killing harmful microbes without damaging the host

5. Representative Sources of Antibiotics Insert Table 20.1

6. Spectrum of Activity • ________________: Antibiotic affects a large number of Gram-positive or Gram-negative bacteria • ________________: Affective against a small range of organisms • Penicillin G affects Gram-positive bacteria but very few Gram-negatives

7. The Spectrum of Activity of Antibiotics and Other Antimicrobial Drugs

8. Spectrum of Activity • Use of broad spectrum drugs also destroy ______ _______________ • Survivors may become _______________ • Yeast infections may arise from the over growth of Candida albicans • _______________ • Term is also applied to growth of a target pathogen that has developed resistance to the antibiotic • Antibiotic resistant strain replaces the original sensitive strain and the infection continues

9. Antibiotics are only effective against ________ infections • ________(flu) and ______________are _____ infections therefore antibiotics are ineffective!

10. Inhibition of Cell Wall Synthesis • Most common agents prevent cross-linkage of NAM subunits • Beta-lactams are most prominent in this group • Functional groups are beta-lactam rings • Beta-lactams bind to enzymes that cross-link NAM subunits • Bacteria have weakened cell walls and eventually lyse

11. Inhibition or degrading bacterial cell walls. Tetrapeptide side chain N-acetylglucosamine (NAG) N-acetylmuramic acid (NAM) Peptide cross-bridge Side-chain amino acid Cross-bridge amino acid NAM Peptide bond Carbohydrate “backbone” NAG Structure of peptidoglycan in gram-positive bacteria .

12. Inhibition or degrading bacterial cell walls. • Penicillin's • Cephalosporin's • Vancomycin

13. The inhibition of bacterial cell synthesis by penicillin. Rod-shaped bacterium before penicillin. The bacterial cell lysing as penicillin weakens the cell wall.

14. One of the most successful groups of antibiotics targets the synthesis of bacterial cell walls; why does the antibiotic not affect the mammalian cell?

15. The inhibition of protein synthesis by antibiotics. Protein synthesis site Growing polypeptide Tunnel Growing polypeptide 50S 5′ Chloramphenicol Binds to 50S portion and inhibits formation of peptide bond 30S 50S portion 3′ mRNA Three-dimensional detail of the protein synthesis site showing the 30S and 50S subunit portions of the 70S prokaryotic ribosome Protein synthesis site tRNA Messenger RNA 30S portion Direction of ribosome movement Tetracyclines Streptomycin 70S prokaryotic ribosome Interfere with attachment of tRNA to mRNA–ribosome complex Changes shape of 30S portion, causing code on mRNA to be read incorrectly Translation Diagram indicating the different points at which chloramphenicol, the tetracyclines, and streptomycin exert their activities

16. Inhibitors of Protein Synthesis • Prokaryotic ribosomes are 70S (30S and 50S) • Eukaryotic ribosomes are 80S (40S and 60S) • Drugs can selectively target translation • Mitochondria of animals and humans contain 70S ribosomes • Can be harmful

17. Inhibitors of Protein Synthesis • Chloramphenicol • Broad spectrum • Binds 50S subunit; inhibits peptide bond formation

18. Inhibitors of Protein Synthesis • Aminoglycosides • Streptomycin • Broad spectrum • Change shape of 30S subunit • Can have fatally toxic effects on Kidneys

19. Inhibitors of Protein Synthesis • Tetracyclines • Broad spectrum • Interfere with tRNA attachment • Side effects? Should Children take tetracycline? • Children may experience a brown discoloration of teeth • Pregnant women may cause liver damage • Most common antibiotic added to animal feed • Use results in significantly faster weight gain

20. Inhibition of nucleic acid replication and transcription

21. Inhibitors of Nucleic Acid Synthesis • Several drugs block DNA replication or mRNA transcription • Drugs often affect both eukaryotic and prokaryotic cells • Not normally used to treat infections • Used in research and perhaps to slow cancer cell replication

22. Inhibitors of Nucleic Acid Synthesis • Rifamycin • Inhibits RNA synthesis • Antituberculosis

23. Injury to the plasma membrane of a yeast cell caused by an antifungal drug.

24. Injury to the Plasma Membrane • Some drugs form channel through cytoplasmic membrane and damage its integrity • PolymyxinB • Topical • Combined with bacitracin and neomycin in over-the-counter preparation

25. Inhibiting the Synthesis of Essential Metabolites: Antimetabolics • Antimetabolic agents can be effective when metabolic processes of pathogen and host differ • Sulfonamides (sulfa drugs) • Inhibit folic acid synthesis • Broad spectrum

26. Inhibiting the Synthesis of Essential Metabolites: Antimetabolics

27. Figure 5.7bc Enzyme inhibitors. Action of Enzyme Inhibitors Competitive inhibitor Altered active site Noncompetitive inhibitor Allosteric site

28. Major Action Modes of Antimicrobial Drugs. 1. Inhibition of cell wall synthesis: penicillins, cephalosporins, bacitracin, vancomycin 2. Inhibition of protein synthesis: chloramphenicol, erythryomycin, tetracyclines, streptomycin DNA mRNA Protein Transcription Translation Replication Enzyme 4. Injury to plasma membrane: polymyxin B 5. Inhibition of essential metabolite synthesis: sulfanimide, trimethoprim 3. Inhibition of nucleic acid replication and transcription: quinolones, rifampin

29. Clinical Considerations in Prescribing Antimicrobial Drugs Routes of Administration Topical application of drug for external infections Oral route requires no needles and is self-administered Intramuscular administration delivers drug via needle into muscle Intravenous administration delivers drug directly to bloodstream

30. Administration method Oral Figure 10.13 The effect of route of administration on blood levels of a chemotherapeutic agent Intramuscular(IM) Relative concentration of drug in blood Continuousintravenous(IV) Time (hours)

31. Clinical Considerations in Prescribing Antimicrobial Drugs Safety and Side Effects Toxicity Cause of many adverse reactions poorly understood Drugs may be toxic to kidneys, liver, or nerves Consideration needed when prescribing drugs to pregnant women Allergies Allergic reactions are rare but may be life threatening Anaphylactic shock

32. Figure 10.14 Some side effects resulting from toxicity of antimicrobial agents-overview Black hairy tongue caused by antiprotozoan drug metronidazole (Flagyl) Temporary and Harmless! Discoloration and damage to tooth enamel caused by tetracycline

33. Resistance to Antimicrobial Drugs • The Development of Resistance in Populations • Some pathogens are naturally resistant • Resistance by bacteria acquired in two ways • New mutations of chromosomal genes • Acquisition of R-plasmids via transformation, transduction, and conjugation

34. Antibiotic Resistance • Misuse of antibiotics selects for resistance mutants • Misuse includes:

35. Clinical Focus Antibiotics in Animal Feed Linked to Human Disease, Figure A. Cephalosporin-resistance in E. coli transferred by conjugation to Salmonella entericain the intestinal tracts of turkeys. S. enterica after conjugation S. enterica E. coli Resistance plasmid

36. Antibiotic Resistance • At least 6 mechanisms of microbial resistance

37. Effects of Combinations of Drugs • __________occurs when the effect of two drugs together is greater than the effect of either alone • ___________occurs when the effect of two drugs together is less than the effect of either alone

38. Figure 20.23 An example of synergism between two different antibiotics. Area of synergistic inhibition, clear Area of growth, cloudy Disk with antibiotic amoxicillin-clavulanic acid Disk with antibiotic aztreonam