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

Table 20.1

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

www.textbookofbacteriology.net

• 1928 – Fleming discovered penicillin, produced by Penicillium (mold)

• First clinical trials in early 1940s

Figure 20.1

Table 20.2

Broad-spectrum antibiotics: those that affect a broad range of gram-positive and/or gram-negative bacteria

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

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:Cell Wall Synthesis

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/images/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

• 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

Effects of Combinations of Drugs

Figure 20.22

• 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

Antibiotic Resistance

http://www.fda.gov/cvm/antiresistvideo.htm

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

Antibiotic Administration

Extinctionof the whole

bacterial population

-Sensitive cells die-Resistant cells die

Evolutionof the surviving

bacterial population

-SELECTIVE PRESSURE-Sensitive cells die

-Resistant cells survive, grow

Appropriate dose/duratio

n

Inappropriate

dose/duration

Infection

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

http://www.mayoclinic.com/images/image_popup/ans7_staph_skin.jpg

MRSA infections: small red bumps deep, painful abscesses

• 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

Antibiotic Resistance

Each of these applies selective pressure on a microbial population, favoring resistant cells.

• FQ approved for use in poultry in 1995

• FQ use discontinued in 2001

www.cdc.gov/ncidod/EID/vol10no6/04-0403-G.htm

Acquisition of fluoroquinolone (FQ)-resistant Campylobacter from poultry.

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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