YSM Issue 90.4

FOCUS
organic chemistry
PUTTING A PATCH ON RESISTANCE:
A total synthesis of pleuromutilin opens the door to new long-lasting antibiotics
by SAM BERRY | art by JASON YANG
You’ve heard the news—bacteria have been quickly evolving immunity to the
antibiotics that we’ve long used to fight them off, and diseases that are now
easily treatable could come back in full force. We desperately need new
antibiotics—yet few pharmaceutical companies are willing to invest in developing
a product that natural selection will so quickly render obsolete.
That’s why a team of Yale chemists,
including chemistry professor Seth
Herzon, postdoctoral associate Stephen
Murphy and graduate student Mingshuo
Zeng, have come up with a new way to
synthesize the antibiotic pleuromutilin,
known to slow the process of bacterial
resistance. It isn’t the antibiotic itself
that was significant about the discovery—it’s
been around for decades—but
rather the process of creating it, which
potentially will allow scientists to create
more potent forms of the drug. By devising
a new synthetic scheme for pleuromutilin,
they have opened the doors
for a new world of potential antibiotics
that can provide us new weapons in the
fight against resistance.
Our antibiotic world
We’ve all grown up in an antibiotic
world. Ever since Alexander Fleming’s
accidental discovery of penicillin in
1927, lifespans have grown longer and
many diseases across the developed
world have been all but eradicated. But
even as antibiotics have changed the
way that we live our lives, a new threat
has begun to emerge. Rampant antibiotic
use promotes the survival and
proliferation of bacteria with special
mutations in their genes that
render antibiotics ineffective.
Over time, more and
more strains of antibiotic-resistant
bacteria begin
to appear as only those with
protective mutations survive rounds of
antibiotic treatment.
Though we desperately need
new antibiotics to counter the rising
threat of resistance, this isn’t
happening. There are fewer and
fewer new antibiotics being developed.
“The reason that we
have so much resistance and
no new drugs is this really
weird, twisted conflation
of economics and
evolution,” Herzon said.
Antibiotics aren’t like
other drugs: patients
usually only use them
for short periods of time, and existing
ones are, in Herzon’s words, “dirt cheap.”
And worst of all, antibiotics often last
only a few years before resistance develops
in bacteria, making the actual lifetime
of an antibiotic much shorter than
that of other drugs.
“The result is that there’s a terrible
downward economic pressure not to do
this,” Herzon said of antibiotic development.
And while funding has increased
slightly for small biotech startups in the
past few years, far more new antibiotics
are needed than are currently being
made.
A longer-lasting antibiotic
In 1951, researchers at Columbia first
isolated a powdery white substance from
the edible mushroom Pleurotus mutilis
and showed that it had antibacterial
properties, naming it pleuromutilin. It
was not until 2007, just as the antibiotic-resistant
bacterial strain MRSA was
making a global appearance in a major
outbreak, that the very first antibiotic
derived from pleuromutilin, retapamulin,
was approved for human use. But retapamulin
is different from other antibiotics:
as of 2014, no bacterial resistance
against the drug has emerged during the
seven years that it’s been on the market.
This is a much longer lifespan than the
couple of years most antibiotics last before
emerging resistance makes them
obsolete.
This key property is likely a result of
a special mechanism of action unique
to this compound. Pleuromutilin and
its derivatives function by binding to an
important region of the ribosome, the
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