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A second program seeks to overcome
some of the more virulent bugs by inhibiting
bacterial DNA replication, the organism’s
means of reproducing and sustaining
an infection. Replidyne has identified a series
of compounds that inhibit replication
and hopes to select one IND candidate by
the end of the year.
Cubist, with one successful drug under
its belt, is probably in the best position
among the small biotechs to move beyond
the natural products approach and into
novel drug discovery techniques. The
company is incorporating computational
chemistry, chemoinformatics, and structure-based
drug design into R&D.
AT THE SAME TIME, Cubist continues
to exploit compounds found in nature by
improving known drugs and isolating new
compounds that could be engineered into
drugs. That effort is aided by better assays
that can weed out the known antibiotics
that tend to dominate natural product
samples.
Cubist’s Metcalf believes the way forward
is to figure out how to create new libraries
that take into account the differences between
bacterial cells and human cells. Fragment-based
drug design isn’t biased to any
particular type of target, he notes, and can
be a starting point to using structural knowledge
to advance a molecule into a drug.
However, substantial resources will be
required to incorporate new techniques
into antibiotics drug discovery. Usually,
that kind of money comes only from big
pharma. Pfizer, which bolstered its antibiotics
capabilities in 2005 through the
acquisition of Vicuron Pharmaceuticals, is
one of the few major companies with substantial
activities in the area.
Although Pfizer’s lead compound, dalbavancin,
belongs to the same class as vancomycin,
the company is also trying to bring
new technology to bear on antibiotic development.
“I think there’s now opportunity
to marry some technologies,” says Paul S.
Miller, head of antibacterials research at
Pfizer. In recent years, researchers have
been able to get at new organisms, such as
those dwelling at the depths of the ocean or
at extreme temperatures. Simultaneously,
scientists are beginning to understand how
to use genomic tools to manipulate the
genes of an interesting organism to tweak
and improve the molecules it produces.
Furthermore, scientists can revisit the
sample libraries accumulated in decades
past—the stuff found in the backyard, as
Miller puts it—and apply new techniques to
find interesting molecules. Many times, only
a tiny fraction of what was contained within
those soil samples could be cultured, he
notes. Today, the potential exists for using
genome DNA amplification technology to
fish out genes responsible for assembling a
compound. Those genes can then be cloned
in a laboratory organism to determine
WWW.CEN-ONLINE.ORG 19 APRIL 14, 2008
whether it could make an interesting drug.
“The microbial diversity on the planet is
enormous, and we’ve only been able to characterize
the tip of that iceberg,” Miller says.
Interest from big pharma does appear
to be percolating: Merck has several programs
in the early stages of development;
GSK is reportedly active in the area; and
Johnson & Johnson has partnered with the
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