Chemical & Engineering News Digital Edition - Institute of Materia ...

“There are a slew of gram-negatives
that are threats and nothing of
great merit in the pipeline.”
maceuticals and director of the Center for
Adaption Genetics & Drug Resistance at
Tufts University, agrees. “There’s absolutely
no question that gram-negatives are the
threat of today,” he says. “The gram-positives
and MRSA may be called superbugs
because of their virulence and resistance,
but there are still drugs to treat them.”
Levy points to a number of gram-negative
bacteria, particularly Pseudomonas
aeruginosa and Acinetobacter baumannii,
that are susceptible to only one drug—or in
some cases no drugs.
THE LACK OF NEW DRUGS to treat gramnegative
bacteria, doctors say, has a basis in
both business and science. On the business
side, these drugs will treat a smaller patient
population than broad-spectrum antibiotics
and, like all antibiotics, are taken for a
finite period. The limited market and tough
target add up to an uninteresting business
opportunity for many companies.
Then there is the tricky science of developing
new drugs against gram-negative
organisms. The category itself is an indication
of how tough the bacteria are to tackle:
Gram-negative bacteria are so-named
because they have an outer membrane
that doesn’t pick up the crystal-violet dye
used in the stain test to distinguish grampositive
and -negative organisms.
If something as innocuous as a stain
can’t penetrate the cell, imagine trying to
develop a molecule that not only has to get
in but then kill the bacteria, points out Chet
Metcalf, senior medicinal chemist at Cubist
Pharmaceuticals. To do its job, an antibiotic
needs to get past an outer membrane, the
cell wall, and then an inner membrane. The
challenge is the outer membrane.
That membrane is covered with lipopolysaccharides—lipids
that act as a permeability
barrier—and it is packed with
efflux pumps that eject the antibiotic from
the cell. Gram-positive organisms, on the
other hand, lack the outer membrane and
have fewer ways of kicking a drug out.
Worse, gram-negative bacteria excel at
making enzymes that can inactivate drugs.
For example, �-lactamases, enzymes responsible
for resistance to �-lactam antibiotics
such as penicillins and cephalosporins, are
becoming a problem, Talbot says. In some
parts of the world, bacteria making those
enzymes are beginning to extend beyond the
hospital and into the community at large.
“This is a big concern, even for treatment of
more routine infections, such as urinary tract
infections,” Talbot adds.
Given the many barriers that gramnegative
bacteria put up, natural products
offer the best solution for attacking them,
researchers say. The problem is that natural
molecules active against gram-negative
organisms are hard to find. According to
Pfizer’s Miller, if a chemist were to screen
a library of 10,000 promising compounds
against both P. aeruginosa and the grampositive
bacteria S. aureus, anywhere from
10 to 100 molecules would likely be active
against S. aureus but only one against P.
aeruginosa.
Then, when a molecule does show
promise in killing gram-negative bacteria,
it is likely to be more toxic than
molecules active against gram-positive
organisms. “The kind of potent things
you find initially that kill Pseudomonas
also kill Staphylococcus because they’re
simply punching holes in the organism,”
Miller says. That’s a failing strategy, he
adds, because it usually means the compound
will “punch holes in every living
thing it can find.”
This all adds up to a tough chemistry
challenge for drug developers. “Nature
isn’t trying to make a compound with
pleasant medicinal characteristics as its
first step,” observes Thomas R. Parr, chief
scientific officer at Targanta Therapeutics.
The challenge also explains the anemic
industry pipeline of drugs to treat gramnegative
infections. “There are a slew of
gram-negatives that are threats and nothing
of great merit in the pipeline,” Paratek’s
Levy acknowledges.
BOEHRINGER INGELHEIM GMBH
Pharma Chemicals
www.boehringer-ingelheim.com/pharmachemicals
www.pharma-chemicals.com
Email: pharmachemicals@boehringer-ingelheim.com