How does
antibiotic resistance
occur?
When drug resistance occurs, the bacteria has not specifically
changed itself in some way to survive. Random mutations are usually responsible
for drug resistance in bacteria. Fortunately (for the bacteria), these
mutations incur some change in the cell?s structure or metabolism that
allow it to survive in the presence of an antibiotic. When doctors try
to treat an infection of these bacteria, the ones with the mutation have
an advantage and will survive to pass on their new genetic information
on to other generations of bacteria. Often, these mutations occur in bacteria
that are harmless, but they have the ability to transfer these genes onto
more virulent bacteria that are more harmful to humans. These transfers
of genetic material can happen through three mechanisms1:
-
Conjugation: this is direct cell-to-cell contact between
two cells through what is called a "conjugation tube". This tube allows
for the transfer of genetic material (DNA, plasmids) to another cell so
that it can integrate the resistance into its genome.
-
Transformation: sometimes when a cell dies the DNA
that is left over can be absorbed by another cell near to it. When the
cell dies, the bacterial wall breaks down and allows the material within
to become accessible to other cells. When this material codes for genetic
resistance to antibiotics, transfer occurs and the new cell is now resistant.
-
Transduction: this occurs when genetic material is
transferred from one cell to another through a bacteriophage. When bacteriophages
infect cells and begin to proliferate in them, some bacterial DNA can sometimes
be incorporated into the viral genome. When the bacteriophages are released
and infect other cells, other cells can become resistant depending on what
bacterial DNA was transferred.
In the last two situations, resistance will only occur if
the genetic material is stably integrated in the host cell. More often
than not, this will occur because these resistance genes are often carried
on portions of DNA called transposons. These fragments of DNA have the
ability to readily integrate themselves into DNA.
(These three methods are illustrated
in Scientific American. Click on "picking up resistance genes" under ILLUSTRATIONS.)
Antibiotic resistance can work through several different
mechanisms from altering the cell wall structure to make it impermeable
to the drug to altering the genetic code of enzymes within the cell to
make them less susceptible to the drug. There are three types of antibiotic
resistance2:
Natural or intrinsic resistance
-
Inaccessibility of the target: this can happen when the cell
wall lacks the proper transporter to allow the drug access to the interior
of the cell.
-
Multidrug efflux systems: sometimes cells naturally have
efflux "pumps" that can remove substances that are harmful to the cell.
When the drug can obtain access into the cell, the cell can then recognize
it and remove it before the drug can take action.
-
Drug inactivation: the cell can also have natural enzymes
that can break down the drug before it can be harmful
Mutational Resistance
-
Target site modification: when a spontaneous mutation occurs,
it can sometimes alter the area of a protein that the drug attacks, thus
making the protein resistant to the drug.
-
Reduced permeability or uptake: mutations can change the
cell wall structure to make the cell less permeable to the drug.
-
Metabolic by-pass: sometimes cells can evolve so that they
no longer require the use of a certain metabolic enzyme. If this is an
enzyme that a drug would normally attack, the cell is not affected.
Extrachromosomal or acquired resistance
-
These mechanisms are the same as described above. The difference
is that they are acquired through the processes of conjugation, transformation,
and transduction as described previously.