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obsolete, usually around the time companies
lose interest in finding replacements.
The result is a disheartening cycle in which
scientists barely catch up, only to again fall
behind the disease curve.
SMALL COMPANIES are starting to step
in where big pharma left off. Cubist Pharmaceuticals,
where Eisenstein now serves
as senior vice president of scientific affairs,
saw promise in daptomycin and licensed it
from Lilly in 1997. As Eisenstein enthusiastically
tells it, in six short years, Cubist scientists
managed to solve the dosing problem—giving
a higher dose less frequently
widened the therapeutic window—and
ushered the drug through late-stage trials,
past regulatory authorities, and to the
market. Last year, Cubist raked in $290
million in sales of Cubicin, its brand name
for daptomycin.
Cubist has been the pacesetter for the
cadre of biotechs devoted to developing
new antibiotics; today, companies such
as Targanta Therapeutics, Replidyne,
Optimer Pharmaceuticals, and Paratek
Pharmaceuticals have drugs on the edge
of commercialization. Like Cubist, many
of the tiny biotechs pursuing antibiotics
are built around chemists or physicians
who formerly led anti-infectives R&D and
commercialization efforts at
bigger firms like Lilly, Wyeth,
and Abbott Laboratories that
abandoned the field.
Cubist has proven that a
small company can bring a drug
to market without a partner and
lay the financial groundwork
for a robust new product pipeline.
The company’s Lexington,
Mass., headquarters bustles
with signs of expansion, a clear
reminder of its recent success.
But the industry needs to
make more progress if antibacterial
drug discovery is to
evolve. Much of the late-stage
new product pipeline at biotech
firms consists of molecules
licensed from U.S. or Japanese
drug companies. These molecules
are largely derivatives of
already-marketed compounds
rather than innovative new
classes.
Rather than delve into basic
research, though, biotechs must
focus their limited resources on
their lead compounds—those
well-understood
derivatives of older
drugs. That leaves
few research dollars
for the newer
discovery techniques,
such as
high-throughput
screening,
combinatorial
chemistry, and
structure-based
COVER STORY
HO
HO
O
HN
HN
HN
NH
WWW.CEN-ONLINE.ORG 16 APRIL 14, 2008
O
HO
O
O
O
O
H
N
N
H
drug design, needed to
make molecules from scratch.
OH
Cubist’s expanding headquarters
houses its nascent effort to build
the infrastructure for new technologies to
discover antibiotics. “We just had our first
profitable year,” notes Chet Metcalf, senior
medicinal chemist at Cubist. “Much of our
previous R&D work had gone into Cubicin.
We’re just now able to put profits back into
new molecules.”
Indeed, Lilly’s decision to scrap daptomycin—a
drug that just required a bit more
creative thinking—underscores the particular
challenges of discovering and developing
novel antibacterial compounds. Developing
a new antibiotic is a sisyphean task, thanks
to the dauntingly steep evolutionary hill researchers
must climb. “The organisms we’re
SHRINKING HARVEST After fertile years in the 1940s
and 1950s, development of new antibiotics waned.
Year
introduced
Class of
drug
1935 Sulfonamides
1941 Penicillins
O
O
O
O
H
N
O
NH 2
HN
NH
O
1944 Aminoglycosides Penicillin
1945 Cephalosporins
HO O
1949
1950
1952
O
Chloramphenicol
Tetracyclines
H H
2N Macrolides/
lincosamides/streptogramins
O
N
N
H
S
H H
Keflex
• H2O 1956 Glycopeptides
1957 Rifamycins
O O
1959 Nitroimidazoles
F
OH
1962 Quinolones HN N N
• HCl • H2O 1968 Trimethoprim
2000 Oxazolidinones
2003 Lipopeptides
HN S
SOURCE: Can. J. Infect. Dis. Med. Microbiol. 2005, 16, 159
R
O
O
N
N
H
O
O
O
HO
H
N
NH 2
H 2 N
O
N
H
O
O
N
H
O
O –
Cipro
O
Daptomycin
H
N
O
trying to inhibit have been
around for millions, if
(CH 2 ) 8 CH 3
not billions, of years and
have a 20-minute generation
cycle,” points out
Cubist’s chief scientific
officer, Steven C. Gilman.
That’s a lot of time to devise means of surviving
environmental threats.
And bacteria tolerate the most extreme
conditions on Earth. They live on the floor
of the ocean or at the core of a snowflake.
They thrive in toxin-laden soil deep below
Earth’s surface as easily as in the acidic
turmoil of the digestive tract. Of course,
not all bacteria are pathogenic, but those
that are make formidable adversaries for
medicinal chemists and microbiologists
looking for molecules that can overcome
their natural defense mechanisms.
Then, once researchers beat evolution
and make it to the top of the hill—once
they have found that one mole-
cule that can stop a pathogen—
the ball starts rolling down
again. Resistance is not an “if ”
but a “when,” Gilman says. As
bacteria figure out how to evade
antibiotics, not only does the
entire discovery process start
over but a company’s key revenue
generator loses steam.
To top it off, antibiotics are
among those quaint, old-fashioned
drugs that patients eventually
stop needing. Lilly, for example,
abandoned daptomycin
at a time when it was enjoying
its first taste of billion-dollar
success with Prozac, a depression
treatment that patients
take indefinitely. Such consistency
in generating blockbuster
sales—the kind investors have
come to expect from large
companies—just isn’t the norm
for antibiotics.
Yet scientists can also use
evolution to their advantage.
Bacteria are battling it out with
each other for survival, which