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That may sound odd: surely the point of medicine is to kill bacteria, not to
cultivate them? But trying to
exterminate bacteria has had nasty consequences. An antibiotic kills the weakest
specimens in a
population. Those that are resistant to the drug survive and resume breeding.
Over time, the resistant
strains outnumber the susceptible ones--and the antibiotic becomes useless.
Worries about antibiotic resistance now loom large. Last year, America's Food
and Drug Administration
approved Zyvox, a drug that introduced a new class of antibiotics to patients
for the first time in 25
years. But in April John Quinn, of the University of Illinois at Chicago, and
his colleagues reported in the
Lancet that some people had developed infections resistant to the new drug after
using it for only three
weeks.
In March, America's Centres for Disease Control published a new set of
guidelines for controlling and
reducing the dosage of antibiotics in patients. Agricultural use is a problem,
too. According to the Union
of Concerned Scientists, based in Cambridge, Massachusetts, around 70% of the
antibiotics made in
America go directly to farm animals, because dosed beasts grow larger. The
hordes of antibacterial
soaps and detergents in the shops also increase the pressure on wild bacteria to
evolve resistance.
This state of affairs has a familiar ring to economists, who know it as the
"tragedy of the commons". In
the short term, each group--of doctors, farmers or vigilant
housekeepers--overuses a common
resource, to the detriment of all in the long term. The solution could lie in
exploiting another idea beloved
of economists, game theory, and tailoring it to the constraints imposed by
natural selection. The idea is
to slow the arms race between antibiotics and bacterial evolution, either by
interfering with bacterial
mechanisms of resistance or by suppressing them entirely. Acting defensive
When a bacterium detects a dangerous chemical, it mounts a host of responses.
One of the most
important is to chew up the toxin with custom-made resistance enzymes. The
natural precision of these
enzymes has been a boon to medicine makers over the decades: chemists have been
able to generate
new varieties of antibiotic by tweaking the design of existing compounds just
enough to fool the
enzymes. If the resistance enzyme cannot recognise and destroy the new variety,
the drug can do its
work unhindered.
Natural selection, however, soon catches up. This has prompted researchers to
look for ways to
interfere with the actions of the bacterial enzymes themselves. Gerard Wright
and his colleagues at
McMaster University in Ontario, Canada, found that some resistance enzymes bear
a resemblance to a
family of molecules known as the protein kinases. Because protein kinases seem
to be involved in a
variety of disorders, pharmaceutical and biotechnology companies have been
looking into their
structures for years. The resemblance between the two groups of compounds means
that inhibitors of
protein kinases also inhibit bacterial resistance enzymes. Dr Wright is now
trying to find a way to reverse
bacterial resistance by modifying one of these protein-kinase inhibitors.
Bacteria also safeguard themselves from toxins by turning on an "efflux" system,
a form of cellular
garbage-disposal that ejects any offending substance without further ado. The
efflux mechanism is a
molecule bound to a bacterium's outer membrane. It locks on to the offending
toxin and ejects it through
the membrane. Some species of bacteria have several types of efflux system.
Microcide, a firm based in
Mountain View, California, has found a compound that attacks three of these
systems in Pseudomonas
aeruginosa. As hoped, this compound augmented the potency of antibiotics in mice
infected with this
pathogen.
Eventually, bacteria would evolve around such gimmicks, just as they evolved
around antibiotics. The
only way to stop this evolution is to neutralise the threat they pose without
killing them too quickly in the
process. That would slow down the arms race between the bacteria and the drug
makers, and Michael
Alekshun and Stuart Levy of Paratek Pharmaceuticals in Boston, Massachusetts,
think they have found
a way to do it. They have identified a regulon (a collection of genes whose
expression is regulated by a
single protein) in the genome of Escherichia coli. This regulon controls the
bacteria's defences against
antibiotics.
When E. coli senses a dangerous chemical, a protein called MarA activates this
regulon, which is known
as Mar because its activation confers "multiple antibiotic resistance". Mar
starts up the cell's efflux
system, and also stops the cell from allowing any more threatening molecules in
by halting the production
of porin, a membrane protein that acts as a channel into the cell. Once the
threat subsides, the MarR
(for "Mar repressor") protein turns off the Mar regulon, and the cell returns to
its normal state.
To disguise an antibiotic attack from a bacterium, all that is needed is an
increased concentration of
MarR and a lowered concentration of MarA. This month, at a meeting of the
American Society of
Microbiology in Orlando, Florida, Dr Alekshun and Dr Levy will unveil the
crystal structure of the MarR
protein, a discovery that makes it easier to find molecules that will interact
with it. They have started the
hunt for molecules that will alter its function, and are also analysing a set of
substances that inactivate
MarA.
Initially, the researchers saw controlling the Mar regulon as a means to
increase or restore the potency
of existing antibiotics. That would be good, but would almost certainly result
in the evolution of
resistance in due course. Further experiments, though, produced an unexpected
result. E. coli without
MarA do not form communities.
Usually, as bacteria float past a congenial surface, they adhere to it and form
a mass of accumulated
layers called a "biofilm". In time, they produce a sturdy sugary coat that
guards the biofilm's tenants from
antibiotics. Infections are often the result of biofilms forming on soft
tissues. But in the Petri dish, bacteria
without MarA did not form biofilms. Dr Alekshun and Dr Levy believe that the Mar
regulon must also
control some important process related to biofilm formation.
If the phenomenon occurs in bodies, as well as glassware, then inactivating MarA
would stop infections
forming. Bacteria could not gain a foothold, and the host's immune system could
simply flush them out of
the body. Antibiotics could then be used more sparingly. By the same token,
bacteria could stop racing
to improve as well: because a Mar-based drug would render bacteria harmless but
would not kill them,
it would not impose a strong selection pressure. Just as game theory suggests, a
compromise that
reduces the damage done by both sides can work to their mutual benefit.
Sometimes mercy is more than
its own reward--even when it is shown to germs.
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