Download File - Microbiology

PowerPoint to accompany
Microbiology:
A Systems Approach
Cowan/Talaro
Chapter 12
Drugs, Microbes, HostThe Elements of
Chemotherapy
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Chapter 12
Topics
- Antimicrobial Therapy
- Selective Toxicity
- Survey of Antimicrobial Drug
- Microbial Drug Resistance
- Drug and Host Interaction
2
Antimicrobial Therapy
• Ideal drug
• Terminology
• Antibiotics
3
Important characteristics regarding antimicrobial drugs.
Table 12.1 Characteristics of the ideal antimicrobial drug
4
Important terms related to chemotherapy.
Table 12.2 Terminology of chemotherapy
5
Antibiotics
• Naturally occurring antimicrobials
– Metabolic products of bacteria and fungi
– Reduce competition for nutrients and
space
• Bacteria
– Streptomyces, Bacillus,
• Molds
– Penicillium, Cephalosporium
6
Selective Toxicity
• Drugs that specifically target microbial
processes, and not the human host
cellular processes.
7
Selective Toxicity
•
•
•
•
•
•
Mechanism of action
Bacterial cell wall
Nucleic acid synthesis
Protein synthesis
Cell membrane
Folic acid synthesis
8
The mechanism of action for different antimicrobial drug targets in
bacterial cells.
Fig. 12.1 Primary sites of action of antimicrobial drugs
on bacterial cells.
9
Cell wall synthesis
• Bactericidal
• Cycloserine – inhibits the formation of
the basic peptidoglycan subunits
• Vancomycin – hinders peptidoglycan
elongation
• Penicillin and cephalosporins – binds
and blocks peptidases involved in
cross-linking the glycan molecules
10
Antibiotics weaken the cell wall, and cause the cell to lyse.
Fig. 12.2 The consequences of exposing a growing cell to
antibiotics that prevent cell wall synthesis.
11
The mechanism of cell wall inhibition by penicillins and
cephalosporins.
Fig. 12.3 The mode of action of penicillins and cephalosporins
12
Nucleic acid synthesis
• Chloroquine – binds and cross-links the
double helix
• Other quinolones – inhibits DNA
unwinding enzymes
• Viruses
– Asidothymidine (AZT)
– Analogs of purines and pyrimidines
13
Protein synthesis
• Aminoglycosides
– Binds the 30S ribosome
– Misreads mRNA
• Tetracyclines
– Blocks attachment of tRNA
• Chloramphenicol
– Binds to the 50S ribosome
– Prevents peptide bond formation
14
Examples of different antibiotics and their sites of inhibition on the
procaryotic ribosome.
Fig. 12.4 Sites of inhibition on the procaryotic ribosome
and major antibiotic that act on these sites.
15
Cell membrane
• Polymyxins
– Interact with membrane phospholipids
– Distorts the cell surface
– Leakage of proteins and nitrogen bases
• Anit-fungal
–
–
–
–
Amphoterin B
Forms complexes with sterols in the membrane
Leakage
Can affect human cell membranes (toxicity)
16
Folic acid synthesis
• Sulfonamides (sulfa drug) and
trimethoprim
– Analogs
– Competitive inhibition
– Prevents the metabolism of DNA, RNA,
and amino acid
17
Sulfonamides compete with PABA for the active site on the
enzyme.
18
Fig. 12.5 The mode of action of sulfa drug.
Survey of Antimicrobial Drugs
•
•
•
•
•
•
•
Penicillin
Cephalosporins
Streptomycin
Tetracyline
Sulfomides
Polyenes
Antiviral
19
Important chemotherapeutic agents used to treat infectious
diseases.
Table 12.3 Selected survey o chemotherapeutic agents
in infectious diseases.
20
Important chemotherapeutic agents used to treat infectious
diseases.
Table 12.3 Selected survey o chemotherapeutic agents
in infectious diseases.
21
Important chemotherapeutic agents used to treat infectious
diseases.
Table 12.3 Selected survey o chemotherapeutic agents
in infectious diseases.
22
Penicillin
• Penicillin chrysogenum
• A diverse group (1st, 2nd , 3rd generations)
– Natural (penicillin G and V)
– Semisynthetic (ampicillin)
• Structure
– Thiazolidine ring
– Beta-lactam ring
– Variable side chain (R group)
23
Penicillin continued
• Resistance – if bacteria contain
penicillinases
• Inhibits cell wall synthesis
• Treat streptococci, meningococci, and
spirochete infections
24
The R group is responsible for the activity of the drug, and
cleavage of the beta-lactam ring will render the drug inactive.
Fig. 12.6 Chemical structure of penicillins
25
Cephalosporin
• Cephalosporium acremonium (mold)
• Widely administered today
– Diverse group (natural and semisynthetic)
• Structure
– similar to penicillin except
• Main ring is different
• Two sites for R groups
26
Cephalosporin continued
• Resistant to most pencillinases
• Broad-spectrum – inhibits cell wall
synthesis
• 3rd generation drugs used to treat
enteric bacteria, respiratory, skin,
urinary and nervous system infections
27
The different R groups allow for versatility and improved
effectiveness.
Fig. 12.7 The structure of cephalosporins
28
Aminoglycosides
• Streptomyces and Micromonospora
• Structure
– Amino sugars and an aminocyclitol ring
• Broad-spectrum
• Commonly used to treat bubonic plague
and sexually transmitted diseases
• Inhibits protein synthesis
29
The amino sugars and six-carbon ring (aminocyclitol) are
characteristics associated with streptomycin.
Fig. 12.8 The structure of streptomycin
30
Streptomyces synthesizes many different antibiotics such as
aminoglycosides, tetracycline, chloramphenicol, and erythromycin.
Fig. 12.9 A colony of Streptomyces
31
Tetracycline
• Streptomyces
• Structure –
– Diverse
– complex series of rings
• Broad spectrum and low cost
• Commonly used to treat sexually transmitted
diseases
• Side effects – gastrointestinal disruption
• Inhibits proteins synthesis
32
Chloramphenicol
•
•
•
•
•
•
•
Streptomyces
Structure - nitrobenzene structure
Broad-spectrum
Only made synthetically today
Treat typhoid fever, brain abscesses
Side effects – aplastic anemia
Inhibits protein synthesis
33
Erythromycin
•
•
•
•
Streptomyces
Structure – macrolide ring
Broad-spectrum
Commonly used as prophylactic drug
prior to surgery
• Side effects - low toxicity
• Inhibits protein synthesis
34
Comparison of three broad-spectrum antibiotics tetracycline,
chloramphenicol, and erythromycin.
Fig. 12.10 Structures of three broad-spectrum antibiotics
35
Sulfonamides (sulfa drugs)
• Synthetic drug
• Based on sulfanilamides
• Used in combination with other
synthetics such as trimethoprim
• Commonly used to treat pneumonia in
AIDS patients
• Inhibits folic acid synthesis
36
Attachment of different R groups to the main structural nucleus
enables versatility of sulfonamides.
Fig. 12.11 The structures of some sulfonamides
37
Polyenes
• Antifungal
• Structure – large complex steroidal
structure
• Some toxicity to humans
• Commonly used for skin infections
• Targets the membrane - lost of selective
permeability
38
Comparison of different antifungal drug structures, which include
polyenes, azoles, and flucytosine.
Fig. 12.12 Some antifungal drug structures
39
Other types of antimicrobials
• Antiprotozoan – metronidazole
– Treat giardia
• Antimalarial – Quinine
– malaria
• Antihelminthic – mebendazole
– Tapeworms, roundworms
40
Antiviral
• Limited drugs available
• Difficult to maintain selective toxicity
• Effective drugs – target viral replication
cycle
– Entry
– Nucleic acid synthesis
– Assembly/release
• Interferon – artificial antiviral drug
41
Antiviral drug structures and their mode of action.
Table 12.5 Actions of selected antiviral drugs.
42
Antiviral drug structures and their mode of action.
Table 12.5 Actions of selected antiviral drugs.
43
Antiviral drug structures and their mode of action.
Table 12.5 Actions of selected antiviral drugs.
44
Antimicrobial Resistance
•
•
•
•
•
•
•
Resistance factors
New enzymes
Permeability
Alter receptors
Change metabolic patterns
Natural selection
New approaches
45
Intermicrobial transfer of plasmids containing resistance genes (R
factors) occurs by conjugation, transformation,and transduction.
Fig. 12.13 Spread of resistance factors
46
Different mechanisms that are commonly associated with drug
resistance.
Fig. 12.14 Examples of mechanisms of acquired drug resistance
47
Demonstration of how natural selection enables resistant strains
to become dominant.
Fig. 12.15 The events in natural selection for drug resistance
48
New approaches
• Increase drug resistance requires new
approaches for developing effective
antimicrobials
– Prevent iron –scavenging capabilities
– Inhibit genetic controls (riboswitches)
– Probiotics and prebiotics
49
Drug and Host Interaction
•
•
•
•
Toxicity to organs
Allergic reactions
Suppress/alter microflora
Effective drugs
50
Tetracycline treatments can cause teeth discoloration.
Fig. 12.16 Drug-induced side effect.
51
Disrupting the microflora in the intestine can result in
superinfections.
Fig. 12.17 The role of antimicrobials in disrupting microbial
Flora
52
Summary of antimicrobial drugs, the primary tissues affected, and
the damage produced.
Table 12.6 Major adverse toxic reactions to common drug groups.
53
Effective drugs
• Identify infectious agent
• Sensitivity testing
• Minimum Inhibitory Concentration (MIC)
54
Sensitivity test such as the Kirby-Bauer Test can be used to
determine the effectiveness of a drug by measuring the zone of
inhibition.
Table 12.7 Results of a sample kirby-bauer test
55
An example of the Kirby-Bauer Test.
Fig. 12.18 Technique for preparation and interpretation
of disc diffusion test.
56
The E-test is an alternative to the Kirby-Bauer procedure.
Fig. 12.19 Alternative to the Kirby-Bauer
57
The dilution test is an effective method of determining the MIC.
Fig. 12.20 Tube dilution test for determining the MIC
58
The lower the MIC, the more effective the drug is toward
combating the bacterium.
Table 12.8 Comparative MICs
59