Chapter 13

advertisement
Jacquelyn G. Black
Microbiology: Principles and
Explorations
Sixth Edition
Chapter 13:
Antimicrobial Therapy
Copyright © 2005 by John Wiley & Sons, Inc.
Antimicrobial Agents
• A special group of chemotherapeutic agents
used to treat diseases caused by microbes
• Antibiosis: literally means “against life”
• Antibiotic: A chemical substance produced by
microbes which has the capacity to inhibit or
destroy the growth of bacteria/other microbes
• Synthetic/semi-synthetic drugs
The History of Chemotherapy
• 1910: Paul Ehrlich used Salvarsan to treat
syphilis
• 1935: Gerhard Domagk discovered prontosil,
a red dye, inhibits growth of many grampositive bacteria
• 1936: Ernest Fourneau discovered that the
sulfanilamide portion contained antimicrobial
activity
General Properties of Antimicrobial
Agents
• Selective Toxicity
• The Spectrum of Activity
• Modes of Action
• Side Effects
• The Resistance of Microorganisms
Selective Toxicity
• The antimicrobial agent must harm the
microbes without causing significant
damage to the host
• Toxic dosage level: causes host damage
• Therapeutic dosage level: successfully
eliminates the pathogenic organism if the
level is maintained
Spectrum of Activity
• The range of different microbes against
which an antimicrobial agent acts
• Broad spectrum: Agents effective against
both gram-positive and gram-negative
bacteria
• Narrow spectrum: Agents effective
against a small number of microbes
Spectrum of Activity
Modes of Action
1. Inhibition of cell wall synthesis
2. Disruption of cell-membrane function
3. Inhibition of protein synthesis
4. Inhibition of nucleic acid synthesis
5. Action as antimetabolites
Modes of Action
Inhibition of Cell Wall Synthesis
• Inhibiting cell wall synthesis selectively
damages bacterial and fungal cells
• Penicillin and cephalosporin contain a
structure called a ß-lactam ring
• The ß-lactam ring attaches to the enzymes
that cross-link peptidoglycans and prevent
cell wall synthesis
Bacteria Before Exposure to Penicillin
Bacteria After Exposure to Penicillin
Disruption of Cell Membrane Function
• Certain polypeptide antibiotics, such as
polymyxins
• Act as detergents and distort bacterial cell
membranes
• Bind to phospholipids in the membrane
• Especially effective against gram-negative
bacteria which have an outer membrane
Inhibition of Protein Synthesis
• An example of selective toxicity
• Attack bacterial cells without significantly
damaging animal cells
• Aminoglycoside antibiotics: Tetracycline,
Erythromycin, streptomycin, chloramphenicol
• Bind to the bacterial 30S ribosomal subunit and
interfere with the translation of mRNA
Inhibition of Nucleic Acid Synthesis
• Differences between the enzymes used by
bacterial and animal cells to synthesize
nucleic acids
• Antibiotics of the rifamycin family bind to a
bacterial RNA polymerase and inhibit RNA
synthesis
Action as Anti-metabolites
•
Substances that affect the utilization of
metabolites and prevent metabolic
reactions
•
Function in two ways:
1. Competitively inhibiting enzymes
2. Erroneously incorporated into important
molecules such as nucleic acids
Competitive
Inhibition
Nucleic Acid Base Analogs
Kinds of Side Effects
•
The side effects of antimicrobial agents
fall into three general categories:
1. Toxicity
2. Allergy
3. Disruption of normal microbiota
Acquisition of Resistance
Microorganisms normally acquire
antibiotic resistance by genetic changes:
1.Natural Selection
2.Chromosomal Mutation
3.Extrachromosomal Resistance
•R Plasmids or R factors
Method of Detecting Genetic Resistance
Mechanisms of Resistance
1. Alteration of Targets
2. Alteration of Membrane Permeability
3. Development of Enzymes
4. Alteration of an Enzyme
5. Alteration of a metabolic pathway
b-lactamase Effect on Penicillin
Alteration of Targets
• This mechanism usually affects bacterial ribosomes
• The mutation alters the DNA such that the protein
produced or target is modified
• Antimicrobial agents can no longer bind to the
target
• Resistance to erythromycin, rifamycin, and antimetabolites
Enzyme Development
• B-lactamase
• These enzymes are found in various
bacteria
• They catalyze the breaking of the Blactam ring in penicillins and some
cephalosporins
First-Line, Second-Line Third-Line
Drugs
• 1930’s sulfonamides were found to cure the
disease, gonorrhea
• Sulfonamide-resistant strains developed and
penicillin was used as a cure
• Penicillin-resistant strains developed and
spectinomycin was used
• Now there are spectinomycin-resistant strains
of gonorrhea
Effects of Premature Termination of
Antibiotic Treatment
Kirby-Bauer Method of Determining
Microbial Sensitivities to Various Antibiotics
Minimal Inhibitory Concentration (MIC)
Microbial Susceptibility
An Epsilometer (E) Test for Determining
Antibiotic Sensitivity
Inoculating Samples Into Individual Wells
Containing Specific Chemical Agents
Incubator Chamber
Structures of Penicillin and Related
Molecules
Staining of Teeth by Tetracycline
Red Man Syndrome
Agents That Inhibit Protein Synthesis
Agents That Inhibit Nucleic Acid
Synthesis
Agents That Inhibit Cell Wall Synthesis
Agents That Interfere With Cell
Membrane Function
Antimetabolites and Other Agents
Black Hairy Tongue: A Reaction to
Metronidazole (Flagyl)
Antifungal Agents
Antihelminthic Agents
Antiviral Agents
Antiprotozoan Agents
Disrupters of Cell Membranes
• Polymyxins (A, B, C, D, and E)
• Obtained from soil bacterium Bacillus polymyxa
• Usually applied topically, often with bacitracin, to
treat skin infections caused by Pseudomonas
• Internally, can cause numbness in the extremities,
serious kidney damage, and respiratory arrest
Tetracyclines
• Obtained from species of Streptomyces
• Are bacteriostatic, readily absorbed from the
digestive tract, and become widely distributed in
tissues and body fluids
• Have the widest spectrum of activity of any
antibiotics
• However, they destroy the normal intestinal
microbiota and ofter produce severe gastrointestinal
disorders
Interferon's and Immunoenhancers
• Cells infected with viruses produce proteins
collectively referred to as interferons
• These interferon proteins induce neighboring cells
to produce antiviral proteins
• Antiviral proteins prevent these cells from
becoming infected
• Interferons are currently being genetically
engineered and tested as antiviral agents
Double Antibiotic Therapy To Eradicate
Resistant Strain Infections
Download