Transcript Document

Chapter 20:
Antimicrobial Drugs
Antimicrobial Drugs
• Chemotherapy
The use of drugs to treat a
disease
• Antimicrobial drugs
Interfere with the growth of
microbes within a host
• Antibiotic: Substance produced by a microbe
that, in small amounts, inhibits another microbe
Table 20.1
www.textbookofbacteriology.net
• 1928 – Fleming
discovered penicillin,
produced by Penicillium
(mold)
• First clinical trials in
early 1940s
Figure 20.1
Broad-spectrum antibiotics: those that affect a broad
range of gram-positive and/or gram-negative bacteria
Table 20.2
Antimicrobial Drugs:
Selective Toxicity
• Selective toxicity: property of a drug that allows it to
kill microbes without damaging the host cells
─ Takes advantage of differences in cell structure and
metabolism between the microbe and host cells
─ Antibacterials: target prokaryotic structures
◦ Penicillin prevents proper synthesis of peptidoglycan
The Action of Antimicrobial Drugs
• Bactericidal: causes death of bacteria
• Bacteriostatic: prevents growth of bacteria
Targets of Antimicrobial Drugs
Figure 20.2
Targets of Antimicrobial Drugs:
Cell wall synthesis
• Penicillin: weakens bacterial cell walls by inhibiting
the crosslinking of peptidoglycan
─ Peptidoglycan is found only in bacterial cell walls
─ Bactericidal (must be actively growing)
Targets of Antimicrobial Drugs:
Cell Wall Synthesis
Penicillins
─ Natural penicillins
◦ Isolated from Penicillium mold
◦ Narrow spectrum of activity
◦ Susceptibility to penicillinases
(or β–lactamases)
─ Semisynthetic penicillins
◦ Chemically add new side chains
to nucleus in attempt to
− reduce susceptibility to
penicillinase
− extend their spectrum of
activity
Targets of Antimicrobial Drugs:
Cell Wall Synthesis
Penicillins
─ Semisynthetic penicillinase-resistant penicillins
◦ Methicillin was the first
−Resistant strains of staphylococci have become
prevalent: MRSA (methicillin-resistant
Staphylococcus aureus)
Targets of Antimicrobial Drugs:
Protein Synthesis
• Exploit 70S ribosomes of prokaryotic cells
─ Eukaryotic (host) cells: 80S ribosomes
◦ Host side effects due to mitochondrial toxicity (mitochondria: 70S)
Figure 20.4
Targets of Antimicrobial Drugs:
Protein Synthesis
• Tetracyclines
─ Broad spectrum of activity
─ Inhibit the association of tRNAs with the 70S
ribosome
─ Prevent the addition of amino acids to the growing
protein chain
─ Bacteriostatic
http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/i
mages/tetres.gif
Other Targets of Antimicrobial Drugs
• Plasma membranes
─ Drugs increase membrane permeability
• Nucleic acid synthesis
─ May affect mammalian nucleic acid synthesis as well
• Essential metabolite synthesis
─ Competitive inhibitors that prevent production of
metabolites that are essential for growth/survival of
the microbe
Testing effectiveness of antibiotics on bacteria:
Disk-Diffusion Test
• Zone of inhibition diameter reflects susceptibility of test organism
to antibiotic drug
Figure 20.17
Effects of Combinations of Drugs
• Antagonism: the effect of two drugs together is less
than the effect of either alone
• Synergism: the effect of two drugs together is greater
than the effect of either alone
─ i.e. Polymyxin (membrane-disrupting drug) makes it
easier for streptomycin to enter the cell
Effects of Combinations of Drugs
Figure 20.22
Antibiotic Resistance
• Cellular mechanisms of antibiotic resistance:
1. Prevention of penetration of drug into cell
2. Alteration of drug's target site (Mutation)
3. Enzymatic destruction of drug
4. Rapid ejection of the drug (Efflux)
http://www.fda.gov/cvm/antiresistvideo.htm
• Resistance genes are often on plasmids that can be
transferred between bacteria
─ 1968: 12,500 Guatemalans died of Shigella diarrhea
◦ This strain contained a plasmid with resistance to four
antibiotics
Emergence of Antibiotic-resistant
mutant bacteria
• Antibiotic-resistant bacteria replacing the sensitive population
─ Every time an antibiotic is used, sensitive bacteria are killed, and
resistant bacteria may survive and continue to grow (repopulate)
─ Presence of the antibiotic provides selective pressure
◦ Selecting for antibiotic-resistant bacteria
◦ Survival of the fittest
Figure 20.20
Infection
Antibiotic
Administration
Appropriate
dose/duration
Extinction
of the whole
bacterial population
-Sensitive cells die
-Resistant cells die
Inappropriate
dose/duration
Evolution
of the surviving
bacterial population
-SELECTIVE PRESSURE
-Sensitive cells die
-Resistant cells survive, grow
MRSA
• About half of S. aureus infections in US are resistant to
penicillin, methicillin, tetracycline, and erythromycin
• Methicillin-resistant Staphylococcus aureus
─ Frequently used to describe S. aureus strains resistant
to all penicillins
─ “Quite common” in hospitals
─ Current treatment for MRSA is vancomycin, the last
weapon in the arsenal
◦ VRSA was reported in 1997, and is (slowly) on the rise
• As more antibiotics are discovered/synthesized,
bacteria continue to adapt by developing and sharing
antibiotic resistance
MRSA infections:
small red bumps  deep, painful abscesses
http://www.mayoclinic.com/images/image_popup/ans7_staph_skin.jpg
Antibiotic Resistance
• One of the world’s most pressing health problems
• Misuse of antibiotics selects for resistant mutants
Misuse includes:
─ Using outdated, weakened antibiotics
─ Using someone else's leftover prescription
─ Failure to complete the prescribed regimen
─ Using antibiotics for the common cold and other
inappropriate conditions
─ Use of antibiotics in animal feed
Each of these applies selective pressure
on a microbial population, favoring resistant cells.
Acquisition of fluoroquinolone (FQ)-resistant Campylobacter from poultry.
• FQ approved for use in
poultry in 1995
• FQ use discontinued in 2001
www.cdc.gov/ncidod/EID/vol10no6/04-0403-G.htm
Strategies to Reduce Emergence of
Antibiotic-resistant bacteria
• Prescription of antibiotics only when it will likely benefit
the patient
• Use an agent with narrow spectrum of activity when
possible
• Use antibiotics at the proper dose and duration
http://www.nearingzero.net/screen_res/nz149.jpg