|
Recent rapid development of bacterial resistance
against antibiotics has brought bacterial infection back into the
limelight as a serious concern, Blackwell says. Virulent strains like
methicillin-resistant Staphylococcus aureus, often known as MRSA (pronounced
"mir-sa") and once found only in hospitals, have become more common
even as the available arsenal of useful drugs against them dwindles.
"Strains are emerging that are resistant to all
known antibiotics," she says. "This is not a problem that's going to
go away - and actually it's just going to get worse. There's a sense
of urgency."
Such urgency is compounded by the speed at which
some strains are capable of developing resistance, she adds. For
example, bacteria resistant to one of the newest antibiotics,
linezolid, appeared within one year of the drug's approval for use.
Since bacteria can adapt to new drugs so quickly,
Blackwell says the best approach is to try to stay several steps ahead
of the bugs. "No one agent is going to solve this problem," she says.
"We need to continue to develop new molecules all the time."
To maximize their chances of finding new compounds
with antibacterial activity, Blackwell's group, including graduate
students Jennifer O'Neill and Joseph Stringer and former graduate
student Matthew Bowman, designed a way to test large numbers of
molecules quickly and efficiently.
They synthesize molecules directly on a flexible,
paper-like sheet, building from the bottom up by adding ingredients
one at a time to sections of the sheet. The finished array has dozens
of compounds arranged in a grid of dots, each about the size of a
pencil eraser.
They subject each array to a battery of tests,
simultaneously testing the potency of each of the compounds against
various strains of bacteria, including the dreaded MRSA.
In the end, relatively few pass muster - so far,
about two percent - but the ability to synthesize and screen such
large numbers of candidates should still allow them to identify large
numbers of new possibilities. The whole process of building and
testing each batch of 50 to 200 compounds takes less than two days.
The four promising compounds identified so far
appear to kill bacteria, at least in a dish, as effectively as several
antibiotics currently on the market, Blackwell says, but the most
exciting thing about these compounds is that they belong to families
of molecules with previously unknown antibiotic potential. By tapping
into new chemical families, she says, they have found substances that
probably fight bacteria in novel ways - suggesting they may stave off
resistance a bit longer.
"These represent whole new classes of antibiotic
agents," she says. Also promising is their finding that, while their
most potent compounds were able to kill several clinically relevant
bacterial strains, the strongest activity was against MRSA and related
strains, known as Gram-positive bacteria.
Finding that these compounds can kill bacteria is a
good first step, but it is only one step of many on the long road to
drug development, Blackwell says. For now, she will focus on
understanding what makes the newly identified infection-fighters tick.
"How do they work?" she asks. "What features of
compounds are necessary for activity, and can we improve them?"
Even subtle structural variations can mean the
difference between a drug and a dud, but looking at large numbers of
related molecules may help the group find clues about which features
help battle the bugs. With such information, they can aim to actively
tune activity through guided synthesis.
With the new method, "We can gather information on
how to improve them fairly quickly," Blackwell says. "Hopefully we
will find new approaches for anti-bacterial therapies." |
