1. Controlling Microbial Growth in the Body: Antimicrobial Drugs
Chapter 10
Controlling Microbial Growth in the Body: Antimicrobial Drugs

2. The History of Antimicrobial Agents
Chemicals that affect physiology in any manner
Chemotherapeutic agents – drugs that act against diseases
Antimicrobial agents – drugs that treat infections

3. The History of Antimicrobial Agents
Paul Ehrlich
“Magic bullets”
Arsenic compound that killed trypanosomes and another that worked against treponemes
Alexander Fleming
Penicillin released from Penicillium
Antibiotics – antimicrobial agents produced naturally by organisms

4. The History of Antimicrobial Agents
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5. The History of Antimicrobial Agents
Gerhard Domagk
Discovered sulfanilamide in 1932
First antimicrobial agent used to treat wide array of infections
Semi-synthetics
Chemically altered antibiotics that are more effective than naturally occurring ones
Synthetics
Antimicrobials that are completely synthesized in a lab

6. The History of Antimicrobial Agents
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7. Mechanisms of Antimicrobial Action
Key is selective toxicity
Antibacterial drugs constitute largest number and diversity of antimicrobial agents
Fewer drugs to treat eukaryotic infections
Even fewer antiviral drugs

8. Mechanisms of Antimicrobial Action
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9. Mechanisms of Antimicrobial Action
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10. Mechanisms of Antimicrobial Action
Inhibition of Cell Wall Synthesis
Inhibition of synthesis of bacterial walls
Most common agents act by preventing 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. Mechanisms of Antimicrobial Action
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12. Mechanisms of Antimicrobial Action
Inhibition of Cell Wall Synthesis
Inhibition of synthesis of bacterial walls
Semi-synthetic derivatives of beta-lactams
More stable in acidic environments
More readily absorbed
Less susceptible to deactivation
More active against more types of bacteria
Simplest beta-lactams – effective only against aerobic Gram-negatives

13. Mechanisms of Antimicrobial Action
Inhibition of Cell Wall Synthesis
Inhibition of synthesis of bacterial walls
Vancomycin and cycloserine interfere with particular alanine-alanine bridges that link NAM subunits in many Gram-positives
Bacitracin blocks secretion of NAG and NAM from cytoplasm
Isoniazid and ethambutol disrupt formation of arabinogalactan-mycolic acid in mycobacterial species

14. Mechanisms of Antimicrobial Action
Inhibition of Cell Wall Synthesis
Inhibition of synthesis of bacterial walls
Prevent bacteria from increasing amount of peptidoglycan
Have no effect on existing peptidoglycan layer
Effective only for growing cells
No effect on plant or animal cells; no peptidoglycan

15. Mechanisms of Antimicrobial Action
Inhibition 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

16. Mechanisms of Antimicrobial Action
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17. Mechanisms of Antimicrobial Action
Disruption of Cytoplasmic Membranes
Some drugs become incorporated into cytoplasmic membrane and damage its integrity
Amphotericin B attaches to ergosterol in fungal membranes
Humans somewhat susceptible because cholesterol similar to ergosterol
Bacteria lack sterols; not susceptible

18. Mechanisms of Antimicrobial Action
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19. Mechanisms of Antimicrobial Action
Disruption of Cytoplasmic Membranes
Azoles and allyamines inhibit ergosterol synthesis
Polymyxin disrupts cytoplasmic membranes of Gram-negatives; toxic to human kidneys
Some parasitic drugs act against cytoplasmic membranes

20. Mechanisms of Antimicrobial Action
Inhibition of Metabolic Pathways
When differences exist between metabolic processes of pathogen and host, anti-metabolic agents can be effective
Quinolones interfere with the metabolism of malaria parasites
Heavy metals inactivate enzymes
Agents that disrupt tubulin polymerization and glucose uptake by many protozoa and parasitic worms
Drugs block activation of viruses
Metabolic antagonists

21. Mechanisms of Antimicrobial Action
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22. Mechanisms of Antimicrobial Action
Inhibition of Metabolic Pathways
Trimethoprim binds to enzyme involved in conversion of dihydrofolic acid to THF
Humans obtain folic acid from diet; metabolism unaffected
Antiviral agents can target unique aspects of viral metabolism
Amantadine, rimantadine, and weak organic bases neutralize acidity of phagolysosome and prevent viral uncoating
Protease inhibitors interfere with an enzyme (protease) that HIV needs in its replication cycle

23. Mechanisms of Antimicrobial Action
Inhibition of Nucleic Acid Synthesis
Several drugs function by blocking DNA replication or mRNA transcription
Only slight differences between prokaryotic and eukaryotic DNA; drugs often affect both types of cells
Not normally used to treat infections; used in research and perhaps to slow cancer cell replication

24. Mechanisms of Antimicrobial Action
Inhibition of Nucleic Acid Synthesis
Compounds can interfere with function of nucleic acids (nucleotide analogs)
Nucleotide Analogs can distort shapes of nucleic acid molecules and prevent further replication, transcription, or translation
Most often used against viruses; viral DNA polymerases more likely to incorporate and viral nucleic acid synthesis more rapid than that in host cells
Also effective against rapidly dividing cancer cells

25. Mechanisms of Antimicrobial Action
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26. Mechanisms of Antimicrobial Action
Inhibition of Nucleic Acid Synthesis
Quinolones and fluoroquinolones act against prokaryotic DNA gyrase; little effect on eukaryotes or viruses
Other drugs, including rifampin, bind to and inhibit action of RNA polymerase during transcription
Reverse transcriptase inhibitors act against the enzyme, reverse transcriptase, an enzyme HIV uses in its replication cycle
Inhibitor does not harm people because humans lack reverse transcriptase

27. Mechanisms of Antimicrobial Action
Prevention of Virus Attachment
Attachment can be blocked by peptide and sugar analogs of attachment or receptor proteins (attachment antagonists)
New area of antimicrobial drug development

28. Clinical Considerations in Prescribing Antimicrobial Drugs
Ideal Antimicrobial Agent
Readily available
Inexpensive
Chemically stable
Easily administered
Nontoxic and nonallergenic
Selectively toxic against wide range of pathogens

29. Clinical Considerations in Prescribing Antimicrobial Drugs
Spectrum of Action
Broad-spectrum antimicrobials may allow for secondary or superinfections to develop
Killing of normal flora reduces microbial antagonism

30. Clinical Considerations in Prescribing Antimicrobial Drugs
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31. Clinical Considerations in Prescribing Antimicrobial Drugs
Efficacy
Ascertained by
Diffusion susceptibility tests
Minimum inhibitory concentration test
Minimum bactericidal concentration test

32. Clinical Considerations in Prescribing Antimicrobial Drugs
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33. Clinical Considerations in Prescribing Antimicrobial Drugs
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34. Clinical Considerations in Prescribing Antimicrobial Drugs
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35. Clinical Considerations in Prescribing Antimicrobial Drugs
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36. Clinical Considerations in Prescribing Antimicrobial Drugs
Routes of Administration
Topical application of drug if infection is external
Oral – simplest; lower drug concentrations; no reliance on health care provider; patients do not always follow prescribing information
Intramuscular – requires needle; concentration never as high as IV administration
Intravenous – requires needle or catheter; drug concentration diminishes as liver and kidneys remove drug from circulation
Must know how antimicrobial agent will be distributed to infected tissues

37. Clinical Considerations in Prescribing Antimicrobial Drugs

38. Clinical Considerations in Prescribing Antimicrobial Drugs
Safety and Side Effects
Toxicity
Exact cause of many adverse reactions poorly understood
Drugs may be toxic to kidneys, liver, or nerves
Considerations needed when prescribing drugs to pregnant women
Allergies
Although allergic reactions are rare, they may be life threatening
Anaphylactic shock

39. Clinical Considerations in Prescribing Antimicrobial Drugs
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40. Clinical Considerations in Prescribing Antimicrobial Drugs
Safety and Side Effects
Disruption of normal microbiota
May result in secondary infections
Overgrowth of normal flora – superinfections
Of greatest concern for hospitalized patients

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

42. Resistance to Antimicrobial Drugs
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43. Resistance to Antimicrobial Drugs
Mechanisms of Resistance
At least six mechanisms of resistance
Resistant cells may produce an enzyme that destroys or deactivates the drug
Microbes may slow or prevent the entry of the drug into the cell
Alter the target of the drug so it cannot attach or binds less effectively
Alter their metabolic chemistry
Pump the antimicrobial out of the cell before it can act
Mycobacterium tuberculosis produces MfpA protein, which binds to DNA gyrase preventing the binding of fluoroquinolone drugs

44. Resistance to Antimicrobial Drugs
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45. Resistance to Antimicrobial Drugs
Multiple Resistance and Cross Resistance
Pathogen can acquire resistance to more than one drug at a time
Common when R-plasmids exchanged
Develop in hospitals and nursing homes; constant use of drugs eliminates sensitive cells
Superbugs
Cross resistance

46. Resistance to Antimicrobial Drugs
Retarding Resistance
High concentration of drug maintained in patient long enough to kill all sensitive cells and inhibit others so immune system can destroy
Use antimicrobial agents in combination; synergism vs. antagonism

47. Resistance to Antimicrobial Drugs
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48. Resistance to Antimicrobial Drugs
Retarding Resistance
Limit use of antimicrobials to necessary cases
Develop new variations of existing drugs
Second-generation drugs
Third-generation drugs
Search for new antibiotics, semi-synthetics, and synthetics
Bacteriocins
Design drugs complementary to the shape of microbial proteins to inhibit them

49. Resistance to Antimicrobial Drugs
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50. Resistance to Antimicrobial Drugs
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51. Resistance to Antimicrobial Drugs
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52. Resistance to Antimicrobial Drugs
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53. Resistance to Antimicrobial Drugs
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54. Resistance to Antimicrobial Drugs
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55. Resistance to Antimicrobial Drugs
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56. Resistance to Antimicrobial Drugs
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57. Resistance to Antimicrobial Drugs
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58. Resistance to Antimicrobial Drugs
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59. Resistance to Antimicrobial Drugs
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60. Resistance to Antimicrobial Drugs
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61. Resistance to Antimicrobial Drugs
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62. Resistance to Antimicrobial Drugs
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