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

2. Antimicrobial Drugs
“One day we could not save lives, or hardly any lives; on the very next day we could do so across a wide spectrum of diseases.
This was an awesome acquisition of power…”
Walsh McDermott, M.D.
Selective toxicity
Kills bacteria without harming host
Most antibiotics made by
Bacillus
Streptomyces
Penicillium
Cephalosporium

3. Antimicrobial Drugs Chemotherapeutic drugs Antimicrobial drugs
Drugs that act against diseases
Antimicrobial drugs
Drugs that treat infectious diseases
Antibiotic
Chemical produced naturally by a microbe that inhibits or kills another microbe
Semi-synthetic antibiotics
Modified antibiotics to enhance effectiveness
Synthetic drugs – Antimicrobial drugs that are completely manmade

4. Table 10.1

5. List of Antibiotics Generic Name/Brand Names
Common Uses/ Possible side Effects
Mechanisms of Action
List of antibiotics - Wikipedia, the free encyclopedia

6. Principle of Selective Toxicity
Antimicrobial agent must be more toxic to pathogen than to host
Based on differences in structure & metabolism between pathogen & host
Many differences = many options
i.e. bacteria vs. eukaryotic hosts
Fewer differences = fewer options,
i.e. fungi, protozoa & helminths vs eukaryotic hosts
Fewest options = Viruses inside host cell

7. Principle of Selective Toxicity
Ideal antimicrobial drug
A drug that kills harmful microbes without damaging the host
Reality
A drug that is more toxic to microbes than the host; try to limit “side effects” of drug
Therapeutic Index
Measurement of drug toxicity
Ratio of toxic dose to the therapeutic dose
Toxic dose = Therapeutic Index
Therapeutic dose

8. Range of activity of a drug against microbes
Spectrum of Activity
Range of activity of a drug against microbes
Narrow spectrum
Effective against EITHER gram positive OR gram negative microbes
Extended spectrum
Beyond original spectrum
Broad spectrum
Effective against a variety of microbes
Long term use may cause “superinfections”

9. Spectrum of Activity

10. Mechanisms of Action of Antimicrobial Agents
Inhibition of Cell Wall Synthesis
Inhibition of Protein Synthesis
Injury to Cell Membrane
Inhibition of Nucleic Acid Synthesis
Inhibition of Metabolic Pathways
Pearson Animation – Chemotherapeutic Agents Modes of Action

11. Mechanisms of Action of Antimicrobial Agents

12. 1. Inhibition of Cell Wall Synthesis
Antimicrobial drugs block formation of peptidoglycan causing cell lysis
Has no effect on existing peptidoglycan –only works on actively reproducing cells

13. 1. Inhibition of Cell Wall Synthesis
Beta-lactams (penicillin & cephalosporin)
irreversibly bind to enzymes that cross-link NAG-NAM subunits
Vancomycin & cycloserine –
interfere with alanine-alanine bridges that link NAM subunits
Bacitracin
Block secretion of NAG & NAM subunits

14. 1. Inhibition of Cell Wall Synthesis
“Beta Lactam” antimicrobial drugs have a beta lactam ring in the structure
Penicillins and Cephalosporin are the most common beta lactam antimicrobial drugs

15. 1. Inhibition of Cell Wall Synthesis
Semisynthetic beta lactam drugs
use beta-lactam ring and added side chains
provide a broader spectrum of activity and greater resistance to beta-lactamase
Oxacillin, Methicillin (MRSA)
Ampicillin, Amoxacillin, Carbenicillin, Ticarcillin
Augmentin, Timentin
Primaxin (imipenem + cilastin)
Aztreonam

16. Beta Lactam Antibiotic: Penicillins
Figure 20.6

17. 1. Inhibition of Cell Wall Synthesis
Bacitracin-
Topical application (triple antibiotic ointment)
Narrow spectrum - gram-positive bacteria
Vancomycin-
Narrow spectrum – gram positive bacteria
Important "last line" against antibiotic resistant S. aureus (MRSA)
Toxicity – auditory nerve, kidneys
Streptogramins - effective against VRE and VRSA

18. 1. Inhibition of Cell Wall Synthesis
Isoniazid (INH) –
blocks gene for enzyme in mycolic acid synthesis
effective against Mycobacterium tuberculosis
toxic to liver
Ethambutol –
prevents formation of mycolic acid
used in combination with other antimycobacterial drugs

19. 2. Inhibition of Protein Synthesis

20. 2. Inhibition of Protein Synthesis
Aminoglycosides -
Streptomycin, Neomycin, Gentamicin, Tobramycin
broad spectrum – G+ & G-
toxic to kidneys, auditory nerves (deafness)
targets 30S subunit; change shape so cannot read codon correctly

21. 2. Inhibition of Protein Synthesis
Tetracycline & Doxycycline –
Broad spectrum–
G+, G-, mycoplasmas, chlamydia, rickettsias
Adverse Effects –
binds to Ca+, teeth, bones, light sensitivity
Target – tRNA docking site

22. Tetracycline & Doxycycline
Tetracycline causes brown band in developing teeth

23. 2. Inhibition of Protein Synthesis
Chlorampenicol –
Broad spectrum but rarely used except for typhoid fever
Adverse Effects – aplastic anemia in 1/24,000; neurological damage
Targets 50S subunit; blocks enzymatic activity

24. 2. Inhibition of Protein Synthesis
Macrolides –
Erythromycin
Alternative to penicillin- if penicillin allergy
Broad spectrum–G+ & a few G-; Mycoplasma
Zpak – azithromycin
Prevent newborn eye infections
Target – 50S subunit; block movement of mRNA

25. 2. Inhibition of Protein Synthesis
Streptogramins
Synercid
Effective against Gram-positives
Answer to VRE and VRSA
Oxazolidinones
Linezolid
Treatment for MRSA and VRE

26. 3. Injury to the Plasma Membrane
Polymyxin B
Effective against Gram negatives, especially Pseudomonas
Toxic to human kidneys
Topical – Combined with bacitracin and neomycin in over-the-counter preparation
Antifungal drugs:
Amphotericin B (polyene) attaches to ergosterol found in fungal membranes
Azoles inhibit ergosterol synthesis

27. 3. Injury to the Plasma Membrane

28. 4. Inhibition of Nucleic Acid Synthesis
Antimicrobial drugs often affect prokaryotic and eukaryotic DNA due to similar DNA
Antimicrobial drugs (nucleotide analogs) interfere with function of nucleic acids
Most often used against viruses
Viral DNA polymerases more likely to incorporate and synthesize viral nucleic acid more rapidly than host cells

29. 4. Inhibition of Nucleic Acid Synthesis
Nucleotide analogs
Figure 10.7

30. 4. Inhibition of Nucleic Acid Synthesis
Rifampin
Inhibits mRNA synthesis
Effective against Mycobacterium tuberculosis
Causes orange-red body fluids
Quinolones and fluoroquinolones
Ciprofloxacin, Nalidixic acid
Inhibits prokaryotic DNA gyrase
Urinary tract infections, Anthrax (bioterrorism)

31. 5. Inhibition of Metabolic Pathways
Use differences between metabolic processes of pathogen and host
Quinines
interfere with the metabolism of malaria parasites
Heavy metals
inactivate enzymes
Zinc: (Zicam) block attachment of viruses

32. 5. Inhibition of Metabolic Pathways
Sulfonamides (Sulfa drugs)
Broad spectrum
G+, G-, protozoa, fungi; lots of resistance
Rare allergic reactions, anemia, jaundice, mental retardation of fetus if given in last trimester
Urinary tract infections

33. 5. Inhibition of Metabolic Pathways
Sulfonamides (Sulfa drugs)
Competitive enzyme inhibitor
Inhibit production of folic acid
Similar structure to PABA - required for nucleotide synthesis

34. PABA and Sulfonamides
Figure 10.6a

35. Sulfa + Trimethoprim = SXT, Bactrim
Figure 20.13

36. Effects of Combinations of Drugs
Synergism occurs when the effect of two drugs together is greater than the effect of either alone. (sulfa + trimethoprim)
Antagonism occurs when the effect of two drugs together is less than the effect of either alone. (penicillin + tetracycline)

37. Safety and side effects of antibiotics
Toxicity
Kidneys, liver or nerves (polymyxin & aminoglycosides
Fetus (tetracycline)
Allergies – mild to severe
anaphylactic shock by penicillin ingestion
Disruption of Normal Microbiota
GI tract – causes diarrhea
Superinfections – by opportunistic pathogens like Candida albicans and Clostridium difficile

39. Antibiotic Resistance in Bacteria

40. Bacterial Resistance to Antibiotics
Some bacteria are Naturally resistant
Do not have the target site of the antibiotic
Bacteria can Acquire resistance
New mutations of chromosomal genes
Acquire R-plasmids through recombination
Pearson Animation: Antimicrobial Resistance- Origins
Figure Overview

41. Bacterial Resistance to Antibiotics
MDR (multiple drug-resistance) – Staphylococcus, Streptococcus, Enterococcus, Pseudomonas, Mycobacterium, Plasmodium
Called superbugs
Usually resistant to 2-3 drugs
Common when R-plasmids are exchanged
Cross resistance –
resistance to one drug may confer resistance to another
usually when antimicrobial drug is similar in structure

42. Bacterial Resistance to Antibiotics
Bacteria acquire mechanisms of drug resistance in several ways:
1. Produce enzymes that destroy drug
Decrease entry of drug in to cell
Pump drug out of cell before it can act
4. Alter target site of drug
Change metabolic pathway
Pearson Animation: Antimicrobial Resistance: Forms

43. Mechanism of Bacterial Resistance: 1
Mechanism of Bacterial Resistance: 1. Produce Enzymes that Destroy Drugs
Beta lactamase - Penicillinase –
Produced by bacteria which deactivates penicillin
Extended-Spectrum beta-lactamase (ESBL)
ESBLs are capable of hydrolyzing:
Semisynthetic penicillins and cephalosporins
Beta-lactamase inhibitors (e.g. clavulanic acid) generally inhibit ESBL producing strains.

44. Mechanism of Bacterial Resistance: 1
Mechanism of Bacterial Resistance: 1. Produce Enzymes that Destroy Drugs
Penicillinase – Inhibits Beta lactam antibiotics
Figure 20.8

45. Mechanism of Bacterial Resistance:
2. Decrease entry of drug in to cell 3. Pump drug out of cell before it can act by efflux pumps

46. Mechanism of Bacterial Resistance: 4. Alteration of metabolic pathway
Some sulfonamide-resistant bacteria do not require PABA
an important precursor for the synthesis of folic acids and nucleic acids in bacteria inhibited by sulfonamides.
Instead, like mammalian cells, sulfonamide-resistant bacteria utilize preformed folic acid.

47. Mechanism of Bacterial Resistance: 4. Alteration of target site
Alteration of PBP (Penicillin Binding Protein)—the binding target site of penicillins
Mechanisms of quinolone resistance:
Produce proteins that can Bind to DNA gyrase
Mutations in DNA gyrase –
decrease their binding affinity to quinolones (decrease the drug's effectiveness)

48. Common Misconceptions about antibiotics
People are (or become) resistant to antibiotics
Antibiotics cause mutations to make the bacteria resistant
Bacteria that are resistant to antibiotics are stronger than sensitive bacteria

49. Drug Resistance Poor Countries Can’t afford full course of medicines
Drugs don’t require
prescriptions
Counterfeit drugs
Gentamicin:
Works on Pseudomonas

50. Drug Resistance Wealthy Countries
Overuse – in many products like lotion, shampoo, soap, toys, socks, etc.
Over-prescribed
Patients demand when not needed
Prescriptions taken incorrectly
Gentamicin:
Works on Pseudomonas

51. Drug Resistance
50% of antibiotics used in U.S. are for food animals – 90% used to prevent disease before it occurs
Thousands of pounds sprayed on fruit trees
Fed probiotics of bacteria with R-plasmids
Gentamicin:
Works on Pseudomonas

53. Slow the Rate of Resistance
Limit use of antimicrobials
Only prescribe to necessary cases
Complete the prescribed regimen
Toss outdated antibiotics; Do not use others’ drugs
High concentrations of drug
Maintain in patient for long enough time to kill all sensitive cells and inhibit others long enough for immune system to destroy
Use antimicrobial agents in combination
Synergism vs. antagonism
Development of new variations of drugs
Second-generation & Third-generation drugs

54. New Antibiotics
Most antibiotics are developed by pharmaceutical companies.
8-10 years & $800 million to $1.7 billion to develop a new antibiotic, only to lose it to resistance.
More profitable to make antidepressants and drugs for chronic diseases.

55. According to WHO
Patients with infections caused by drug-resistant bacteria
at increased risk of worse clinical outcomes and death
consume more health-care resources than patients infected with the same bacteria that are not resistant
Treatment failures due to resistance to treatments of last resort for gonorrhoea (third-generation cephalosporins) have been reported from 10 countries.
Gonorrhoea may soon become untreatable as no vaccines or new drugs are in development.

56. According to WHO In 2012, gradual increase in resistance to HIV drugs
-further increases in resistance to first-line treatment drugs were reported, which might require using more expensive drugs in the near future
In 2013, there were about new cases of multidrug-resistant tuberculosis (MDR-TB)
. Extensively drug-resistant tuberculosis (XDR-TB) has been identified in 100 countries.
MDR-TB requires treatment courses that are much longer and less effective than those for non-resistant TB.

57. Antibiotic Resistance
“It’s a very real possibility that today’s antibiotics will be rendered useless in 10 to 15 years. We must face the reality of a worldwide problem of ineffective antibiotics.”
Nils Daulaire
President of the Global Health Council
June