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Basic Antibiotic Resistance Strategies
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Antibiotics operate in a number of ways, and how the bacterium
becomes resistant differs accordingly. There are many ways to
slice this particular pie. One is to mention that some resistances
are absolute - no matter how much of a particular antibiotic you
throw at the bacterium it is unphased; while in another slice of
the pie we see that a bacterium might have gained a little
resistance to the antibiotic but not to huge doses of it.
In the first case, the antibiotic might normally attach to some
critical enzyme and inactivate it. The cell dies for want of that
necessary function. Resistance might come about because a mutant
form of that enzyme chanced to come about, and it no longer has the
side-group to which the antibiotic would otherwise attach. Thus,
no matter how much antibiotic there was around, none would attach
to that enzyme to inactivate it. Streptomycin resistance is like
that: one of the protein components of ribosomes is "sticky" for
streptomycin. And when streptomycin sticks to it, the ribosome
cannot move along the mRNA. No transcription, no cell - it dies.
In the second case, the cell might have a little used function
derived from living in a fungi-filled environment where antibiotics
are found in low concentrations. We will focus on penicillin, of which there are many types. All have the portion indicated by the box as shown to the right. The cell normally makes a small amount of enzyme, a β-lactamase, that goes out and destroys that particular type of antibiotic at the bond indicated in the figure to the right. It is a matter mainly of which gets what first: does the enzyme destroy the antibiotic first, or does the antibiotic
sneak past and kill the cell first? Penicillin resistance works
this way. The enzyme penicillinase either shatters the penicillin,
or the penicillin sneaks by and prevents the growing bacterium from
synthesizing its cell wall and the growing cell explodes.
Resistance to higher doses of penicillin comes about because the
cell is able to make more and more penicillinase. Once upon a time
a mere trace of penicillin cured gonnorhea or strep throat. Now it
takes gram quantitites because the bacteria now produce prodigious amounts of the β-lactamase.
Of course some classes of bacteria are totally resistant to penicillin just as you yourself are. That is because those bacteria (the Gram-negative ones) and you do not make cell walls the way Gram-positive bacteria do. G(-) bacteria make a different kind of cell wall, and also hide the one they make inside of an outer membrane. So not only has the penicillin little effect on the G(-) cell wall, but the penicillin can't get at it. This is fortunate because when you have a disease caused by a G(+) penicillin sensitive disease, you can dose yourself with penicillin and not affect the E.coli and other beneficial G(-) bacteria in your intestines. Oh, and you, of course, don't make cell walls in any case, so PEN doesn't affect you.
Then there are analogs such as the sulfa drugs that interfer with
the metabolism of bacteria. These are technically not antibiotics
because they are not produced by fungi or other life forms other
than by humans in the lab. The sulfa drugs are actually types of
yellow dyes. Workers in those facilties were noted for being freer
of certain diseases than most other people. The connection was
made and the sulfa was then administered therapeutically. You
mammalian body cannot be confused by sulfa for the making of folic
acid, a vitamin, because your body requires fully made folic acid.
But a bacterium (and some fungi) mistake sulfa for
para-amino-benzoic acid (PABA), which is a building block for folic
acid. With sulfa around, it feed-back inhibits the pathway that
makes PABA and so no PABA is made, and sulfa is sufficiently
different from PABA that the next building block cannot be added to
it. Sulfa stops metabolism. Resistance comes about with failure
of the feed-back inhibition. If there is no feed-back inhibition,
then PABA is made and the cell life goes on.
It is estimated that in about 1 in 10 million bacterial cells a mutation exists for some degree of resistance to a particular antibiotic. So in a petri plate colony of normal size, there is likely to be one mutant. What is the chance that a cell would be resistant to two different antibiotics? One in 10 million times 10 million. That is why two antibiotics are often given: extremely slim chance of a double mutant. (But if there is just one double mutant cell, overnight that cell can divide and keep making the patient sick or cause death.)
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