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Published online: 4 April 2007; | doi:10.1038/news070402-6
Weak drug combos find new useAntibiotics that don't work could beat back resistant bacteria.John Whitfield 
| Mix and match: some drugs are stronger together, some weaker. Corbis |
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You
would think that a combination of antibiotics that is less effective
than either drug on its own would be fairly useless. But researchers
now say that such ineffectual mixes could be used in the campaign
against resistance to the drugs.
The
counterintuitive conclusion comes from the observation — so far seen
only in the lab — that less-effective drug mixes allow bacteria that
are sensitive to drugs to out-compete those that are resistant them.
Exploiting the trade-off between an antibiotic's ability to kill
bacteria and the pressure it exerts on them to become resistant might
help to overcome the problem of resistance, say Roy Kishony of Harvard
Medical School in Boston and his colleagues.
Because
very few new antibiotics are being discovered, looking at how the
existing ones work in combination could be a fruitful approach, says
microbiologist Bruce Levin of Emory University in Atlanta, Georgia.
"We
are losing the arms race, and something that at least delays the loss
would be useful," he adds. "If we are just counting on new drugs, we
could be screwed."
Together we're weaker
Kishony's
team looked at the effects of doxycycline — an antibiotic used to treat
infections such as plague and syphilis — on the bacterium Escherichia coli.
They tested the antibiotic on bacteria sensitive to the drug, and on
those engineered to be resistant by pumping the antibiotic out.
One
set of trials combined doxycycline with erythromycin. This combination
is synergistic — together, the drugs' effect is greater than the sum of
their individual effects. Not surprisingly, resistant bacteria grew
much better than the sensitive strain under this treatment.
Other
trials used doxycycline and ciprofloxacin. This combination of drugs is
'suppressive' — the two together are weaker than either used
individually, although no one knows why. In this instance both strains
of bacteria grew more quickly than they would when attacked with either
drug alone.
But,
the researchers found, this growth varied depending on how the drugs
were mixed. With a low proportion of doxycycline, the sensitive
bacteria out-grew the resistant ones. In this case, natural selection
should work against antibiotic resistance, they reasoned.
The
team confirmed their theory by setting up competitions between the two
types of bacteria in different drug environments. They found they could
get sensitive strains to out-compete the resistant ones (almost, but
not quite completely, wiping out the hardy strains) with a range of
drug combinations. The scheme also worked against the bacterium Staphylococcus aureus, a widespread and often lethal source of drug-resistant infections, they report in Nature1.
Double whammy
The
results hint that a patient with an antibiotic-resistant infection
could benefit from being treated first with a poor mix of drugs, so
that the sensitive bugs flourish and the resistant ones die out through
competition. A second bout of effective drugs could then clear away the
remaining infection, says Edward Feil, who studies bacterial evolution
at the University of Bath, UK.
Hitting
bacteria with a one-two punch might be particularly useful in small,
localized outbreaks of resistance, he says, such as in individual
patients or hospital wards. But, he adds, finding the right combination
might be hard, and it might not work quickly enough to benefit the
infected patient.
And resistant bacteria might find a way round this effect, as they have for so many other antibiotic assaults, the team adds.
Antibiotics
are not going to become useless, says Feil; there will always be some
bacteria that are susceptible to them. But we are going to have to live
with resistant bugs too, he adds. "There is no obvious way we will get
rid of them in the foreseeable future."
References
- Chait R., Craney A. & Kishony R.. Nature,
446
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668
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671
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