How do antibiotics kill bacteria without harming host cells

18 April 2005

Lecture 39

Reading, Chapter 12, Chapter 13

A. Prokaryotes (and viruses)

4. Human pathogens

Most bacteria and viruses are harmless. Many bacteria are beneficial to humans and the living world. A few cause disease. In the case of bacteria, this is usually a matter of bacterial cells getting into tissues and killing them with poisons that they produce. Viruses destroy cells as part of their life history but they are specific about the organism and cell type that they infect. Most viruses do not infect humans.

a. Bacterial diseases

Some examples of bacterial diseases include:

anthrax

black plague

cholera

dental cares

diphtheria

"gangrene"

gonorrhea

Hansen's disease (leprosy)

pneumonia

"strep throat"

tuberculosis

typhoid fever

These diseases once killed millions annually and are still major killers in the developing world. In the developed world, they are now relatively easy to control with clean water, antibiotics, and sometimes vaccines. Further information about these bacterial diseases is in Table 13.3 on page 301 of your text.

b. Antibiotics

Antibiotics are simply chemicals that kill prokaryotic cells but do not harm eukaryotic cells. They are natural chemicals produced by fungi and bacteria that act to control their bacterial competitors. For example, streptomycin stops protein synthesis in prokaryotic cells by binding to their unusual ribosomes. Streptomycin does not stop protein synthesis in eukaryotic cells because it does not bind to eukaryotic ribosomes. Penicillin and vancomycin inhibit enzymes required for formation of the bacterial cell wall, a structure that bacterial cells have but animal cells do not.

(The first antibiotic, penicillin, was discovered when Alexander Fleming noticed that a fungal contaminant in his bacterial culture was killing the bacteria. Instead of throwing the "bad" culture plate away, he learned from it and changed the world. This has become a parable on the value of having a prepared mind in the sciences. Fleming realized in a moment that his "accident" had shown him something he could never have found intentionally.)

c. Vaccines

These are mixtures of proteins and other substances that train your immune system to recognize a particular foreign protein and destroy it. Once trained, your immune cells attack and destroy viral particles in your blood and tissues. Aggressive programs of vaccination have been used to eradicate terrible viral diseases such as smallpox and polio.

d. Antiobiotic resistance 

Like all living things, bacteria experience random changes in their genome. Some of the changes are beneficial and improve reproduction under the prevailing selective environment. If the selective environment includes antibiotics, eventually, a mutation will occur that confers resistance to the antibiotic and the descendants of that bacterium will survive better than non-resistant strains.

Mutations that confer antibiotic resistance typically cause one of three things: alteration of the binding site of the antibiotic on the protein that it normally interferes with, alteration of an enzyme such that it degrades the antibiotic, or alteration of a transporter protein such that the antibiotic is exported from the cell.

Widespread use of antibiotics has led to the appearance of many antibiotic-resistant strains of bacteria. This threatens to make bacterial disease major killers once again. At present, 70% of bacterial infections acquired in hospitals are antibiotic-resistant. The death rate from such infections, while still low, has increased 8-fold in the last 10 years.

 There are several steps that can be taken to slow the appearance of antibiotic-resistant bacteria:

1) Do not over-prescribe antibiotics. They are useless against viral infections such as colds and flu and simply favor the evolution of resistance when used unnecessarily.

2) Use antibiotics in combination. The chances of random mutations conferring resistance to two different drugs at once are very small.

3) Finish your medicine. Weak or short treatments of antibiotics allow mildly resistant bacteria to survive. Strong treatments can kill them even if they are mildly resistant. Always finish your antibiotic prescriptions as instructed, even if you feel well.

4) Discover new drugs. This is happening too slowly and must be accelerated.

e. Viral diseases

Viral pathogens differ from bacterial ones in that the antibiotics that kill bacteria do not work against viruses. There are very few antiviral drugs. One reason for this is that viruses only grow when they are inside your cells. Most of the chemicals that would stop their growth would do so by killing your cells. There are very few viral proteins for drugs to bind with and inhibit. Viruses offer very few "drug targets" because they are so simple.

Viral infections can be prevented by vaccines. These are mixtures of proteins and other substances that train your immune system to recognize a particular foreign protein and destroy it. Once trained, your immune cells attack and destroy viral particles in your blood and tissues. Aggressive programs of vaccination have been used to eradicate terrible viral diseases such as smallpox and polio.

Poliovirus

Poliovirus is an example of a viral pathogen. It is a very small virus that has a strand of RNA for its chromosome. It recognizes, binds to, and infects spinal nerve cells. It exhibits an aggressive lytic cycle, destroying the host cell in 6 to 10 hours. Upon infection, it takes over protein synthesis of the host cell completely. Only viral proteins are synthesized after infection.

Poliovirus destroys spinal nerves and can cause paralysis and death. On average, 25% of polio cases become disabled. Polio infection occurs when poliovirus is ingested with dirty water, e.g. at the swimming hole. In 1954, there were 60,000 cases of polio and 3,000 deaths from the disease. In the present, polio is nearly extinct. Aggressive vaccination and water treatment has abolished the disease world-wide. Vaccinations may be discontinued as early as 2005.

HIV

Some viral diseases are not easily prevented with vaccination. The worst of these is the Human Immunodeficiency Virus (HIV) that causes Acquired Immuno-Deficiency Syndrome (AIDS).

HIV attacks cells of the immune system so that the victim becomes very susceptible to other diseases. A yeast infection can become fatal. At present it is estimated that more than 40 million people are infected with HIV world-wide, more than the number of people killed during World-War II. All will die of this disease, though new combinations of anti-viral drugs can prolong their lives significantly.

HIV specifically infects CD4+ helper T cells of the immune system. These cells trigger immune responses and loss of them suppresses the immune system, leading to death by other infections.

HIV is a "retrovirus". This means that its chromosome is composed of RNA rather than DNA. Its life cycle has the following steps:

1. HIV enters the bloodstream by contact of body fluids from an infected individual with the bloodstream of the victim.

2. HIV infects T cells in the blood by binding to a particular "receptor" protein on the T cell surface and injecting its RNA into the cell. Once inside the T cell, the viral RNA is copied into DNA by a viral enzyme called reverse transcriptase.

3. The DNA copy of the HIV chromosome adds itself to the chromosome of the infected cell, where it remains latent or nearly latent for an average of 8 years. During this latency period, the victim shows few or no symptoms but can infect others and will test positive for HIV infection.

4. At some point, the latent HIV becomes fully active. The viral genes in the host cell chromosome begin making the RNA and proteins for new HIV. The proteins are cut to the proper length by a viral protease and the RNA and proteins are packaged into new viruses. The new viruses leave the T cell, killing it. The new viruses go on to infect more T cells.

An excellent animation of the HIV life cycle can be viewed at

HIV life cycle

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