Chapter 20: Antimicrobial Drugs

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Chapter 20Antimicrobial Drugs
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Antimicrobial Drugs

• Chemotherapy The use of drugs to treat a
  disease
• Antimicrobial drugs Interfere with the growth of
  microbes within a host

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• Antibiotic Substance produced by a microbe
  that, in small amounts, inhibits another microbe

Table 20.1
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www.textbookofbacteriology.net
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• 1928 Fleming discovered penicillin, produced
  by Penicillium (mold)
• First clinical trials in early 1940s

Figure 20.1
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Broad-spectrum antibiotics those that affect a
broad range of gram-positive and/or gram-negative
bacteria
Table 20.2
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Antimicrobial DrugsSelective 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

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The Action of Antimicrobial Drugs

• Bactericidal causes death of bacteria
• Bacteriostatic prevents growth of bacteria

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Targets of Antimicrobial Drugs
Figure 20.2
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Targets of Antimicrobial DrugsCell 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)

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Targets of Antimicrobial DrugsCell Wall
Synthesis

• Penicillins
• Natural penicillins
• Isolated from Penicillium mold
• Narrow spectrum of activity
• Susceptibility to penicillinases (or
  ßlactamases)
• Semisynthetic penicillins
• Chemically add new side chains to nucleus in
  attempt to
• reduce susceptibility to penicillinase
• extend their spectrum of activity

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Targets of Antimicrobial DrugsCell Wall
Synthesis

• Penicillins
• Semisynthetic penicillinase-resistant penicillins
• Methicillin was the first
• Resistant strains of staphylococci have become
  prevalent MRSA (methicillin-resistant
  Staphylococcus aureus)

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Targets of Antimicrobial DrugsProtein Synthesis

• Exploit 70S ribosomes of prokaryotic cells
• Eukaryotic (host) cells 80S ribosomes
• Host side effects due to mitochondrial toxicity
  (mitochondria 70S)

Figure 20.4
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Targets of Antimicrobial DrugsProtein 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/images/tetres.gif
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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

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Testing effectiveness of antibiotics on
bacteriaDisk-Diffusion Test

• Zone of inhibition diameter reflects
  susceptibility of test organism to antibiotic drug

Figure 20.17
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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

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Effects of Combinations of Drugs
Figure 20.22
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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)
• 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

http//www.fda.gov/cvm/antiresistvideo.htm
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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
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Infection
Antibiotic Administration
Inappropriate dose/duration
Appropriate dose/duration
Evolution of the surviving bacterial
population -SELECTIVE PRESSURE -Sensitive cells
die -Resistant cells survive, grow
Extinction of the whole bacterial
population -Sensitive cells die -Resistant cells
die
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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

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MRSA infections small red bumps ? deep, painful
abscesses
http//www.mayoclinic.com/images/image_popup/ans7_
staph_skin.jpg
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Antibiotic Resistance

• One of the worlds 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.
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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
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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

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