|
Introduction
Rifampicin is a naturally made,
non-peptide antibiotic. It is bactericidal, killing by
disabling the protein expression system universally conserved by
all bacteria. Specifically, rif inhibits the RNA polymerase
protein, which is responsible for binding to a strand of DNA as
a template and using it to construct a strand of mRNA
Rifampicin inhibits RNA polymerase
by bonding tightly in the RNA exit channel. Therefore, after
transcription begins, the RNA transcript, trying to exit the
RNAP through the exit channel, runs into the rifampicin sitting
in the middle of the channel. This effectively halts
transcription when the RNA transcript is merely two or three
nucleotides in length.
Despite this highly efficient
method for killing bacteria, rifampicin is by no means a perfect
antibiotic. The biggest problem arises from the fact that
bacteria can easily acquire strong resistance or even immunity
to rifampicin through a variety of mutations, most of them a
single amino acid substitution. The problem is an interesting
paradox, since the reason rifampicin works so well is that it is
a rigid molecule, and sits tightly in the pocket where it binds,
allowing the bonds to be very strong. However, this also means
that if an amino acid on the edge of the channel with a small
sidechain is replaced with an amino acid with a large sidechain,
rifampicin may not be able to bind, simply because it cannot fit
in the space. This occurs in three primary positions, one of
which occurs 9% of the time, another of which occurs 36% of the
time, and the last of which occurs an alarming 41% of the time.
Because
bacteria gains immunity to rif in a relatively short amount of
time, it used only in very special circumstances in an effort to
keep bacteria vulnerable to rif, hopefully making it effective
when it does need to be used. The most common usage of rif is
as part of a tuberculosis therapy program. Tuberculosis (TB) is
an extremely contagious, extremely lethal bacterial disease,
which often lurks in the lungs until the host has a weakened
immune system, at which time it manifests itself, resulting in
symptoms which are debilitating at best. In fact, TB remains
the leading cause of preventable death by a pathogen in the
world. However, unless the bacteria is immune already,
rifampicin is very effective, cutting the therapy time from two
years down to six months. The problem is that with cases in the
US declining to the point of nonexistence, pharmaceutical
companies no longer see it as a source of profit, and all but
three have ceased making it, even though TB is still common
among people in developing countries, who are unable to pay for
the treatment. In fact, the three that are still making it are
only doing so because they are being forced to do so by the
World Health Organization. |