4
BioTech Navigator, March 1998
come the toxicity, but retain the an-
tibiotic profile. This is not impossi-
ble, but it will take some time and
money. BTN likes the structure-based
drug design approach that Cubist is
undertaking, but is cautiously opti-
mistic about Daptomycin.
Other biotech and pharmaceutical
companies are looking at natural an-
tibiotics that can be obtained from a
variety of sources. For example, Ma-
gainin is in clinical trials with a pep-
tide, Cytolex, which is derived from
frog skin. The idea to look at frog
skin for antibiotics came from a scien-
tist that noticed frogs with open
wounds never got infections, even
though the tanks that they were kept
in harbored bacteria. A pivotal Phase
III clinical trial of Cytolex, was initi-
ated in March 1997 for the treatment
of infection in diabetic foot ulcers.
Magainin reported successful results
from a second such pivotal trial.
These trials were designed as equiva-
lence studies with the goal of demon-
strating that Cytolex topical cream is
as effective as orally administered
ofloxacin, a quinolone antibiotic, indi-
cated for the treatment of skin and
soft tissue infections. Magainin's
analysis of the data from the studies
showed statistical equivalence be-
tween Cytolex and ofloxacin, with
respect to the primary end point of
clinical response of infection at day
10 of treatment, and at subsequent
time points through day 28, and at
follow-up. The two studies together
enrolled approximately 925 patients.
BTN are impressed with these natural
antibiotics, and strongly believe that
they will make contributions to the
antibiotic sector, leading to profits for
those investors that have patience and
are willing to go the distance.
The bulk manufacturing of these
types of compounds versus traditional
antibiotics for therapeutic use is com-
plicated and will require a significant
outlay of cash. Magainin does not
have the resources, facilities or capa-
bilities to manufacture any of its pro-
structure-based drug design approach
to develop antibacterial compounds
targeted against a bacterial enzyme
required for protein synthesis. The
enzyme is that they are focusing on
are aminoacyl-tRNA synthetases,
which are significantly different
enough from the cellular enzyme that
compounds should not be toxic. Cu-
bist's bacterial aminoacyl-tRNA syn-
thetase program, which now includes
over 100 biological assays, has identi-
fied and selected targets against
which multiple compounds have
demonstrated inhibitory activity. Cu-
bist has advanced these targets
through high throughput screening.
Cubist has also identified some dis-
tinct chemical series that have broad
spectrum activity, 100 fold or greater
selectivity relative to the correspond-
ing human enzyme and single-digit
values against S. aureus and Entero-
coccus species. Compounds that in-
hibit more than one synthetase target
have been identified and are being
followed up for their potential to im-
pede the emergence of drug resistant
variants. A number of these bacterial
lead molecules are also the focus of
chemistry lead optimization pro-
grams. This approach has drawn the
attention of both Merck and Bristol-
Myers-Squibb, as they have estab-
lished collaborations with Cubist, to
screen their library of compounds for
leads in exchange for rights to any
product.
In addition to their research and
development program, Cubist re-
ceived worldwide rights from Eli Lilly
and Company to develop, manufac-
ture and market Daptomycin to treat
bacterial infections that are resistant
to vancomycin. Daptomycin is a nat-
urally occurring antibiotic that has
excellent antibiotic properties in the
laboratory, but is toxic in animals and
humans. Initially, Eli Lilly dropped
this program because of the toxicity
associated with treatment in humans.
Cubist is hoping that they can modify
the dosage and administration to over-
Many pharmaceutical companies
are pursuing the development of drugs
to inhibit mechanisms of antibiotic
resistance. Determining the structure
of resistance molecules should enable
drug designers to build inhibitors of
these molecules. This is referred to as
structure-based drug design and has
been successful applied in creating
compounds capable of inhibiting the
most formidable infectious agents,
such as the human immunodeficiency
virus (HIV). The structure of the en-
zyme that is responsible for inactivat-
ing penicillin, beta-lactamase, has
been determined and companies such
as Pfizer, SmithKline Beecham, and
Lederle Laboratories, have attacked
this enzyme. Beta-lactamase in-
hibitors, such as clavulanate, sulbac-
tam, and tazobactam, when adminis-
tered along with penicillin can extend
the useful life of the antibiotic. Like-
wise, it may be possible to counter
tetracycline resistance by administer-
ing the drug with an agent capable of
blocking the tetracycline pump; re-
search is under way to develop pump
inhibitorsfor clinical use. Research is
also under way to develop a drug to
block isoniazid-resistance in My-
cobacterium tuberculosis. Scientists
at the Albert Einstein College of
Medicine cloned the gene that makes
M. tuberculosis resistant to isoniazid.
Investigators have purified the protein
and determined its structure and func-
tion. Biotech and pharmaceutical
companies should be interested in this
important discovery. Discovery of
such molecules that can inhibit the
resistance gene products could return
original cache of antibiotics to their
original glory. However, some scien-
tist and physicians think that these
approaches are just delaying the in-
evitable and that new antibiotic need
to be discovered.
Search for new antibiotics:
Cubist Pharmaceuticals is taking a
