Researchers uncover survival technique of staph

RESEARCHERS have determined the structure
and mechanism of an enzyme that
performs the crucial first step in the
formation of cholesterol and a key virulence
factor in staph bacteria.
Chemists at the University of Illinois and
collaborators in Taiwan studied a type of
enzyme found in humans, plants, fungi,
parasites, and many bacteria that begins the
synthesis of triterpenes - one of the most
abundant and most ancient classes of
molecules. Triterpenes are precursors to
steroids such as cholesterol.
“These enzymes are important drug
targets,” said Chemistry Prof. Eric Oldfield,
who co-led the study.
“Blocking their activity can lead to new
cholesterol-lowering drugs, antibiotics that
cure staph infections, and drugs that target
the parasites that cause tropical maladies
such as Chagas disease - a leading cause of
sudden death in Latin America. ”
For the study, the team picked a
representative enzyme, dehydrosqualene
synthase (CrtM), from the Staphylococcus
aureus bacterium. Staph is one of the most
common, yet notoriously hard to kill,
bacterial infections.
A key reason for staph’s resilience is a
golden-colored coating called
staphyloxanthin that protects it from the
body ’s immune system. CrtM catalyzes the
first reaction in making staphyloxanthin, so
inhibiting it would strip the bacteria of their
protective coats and leave them vulnerable
to attack by white blood cells.
The researchers already knew what CrtM
looked like and its end product, but they
didn ’t know how the enzyme did its job.
Uncovering the mechanism of action would
enable scientists to design better inhibitors,
and even tailor them to other targets.
The team crystallised the enzyme and
soaked it with intermediates and inhibitors.
They then studied the complex structures
by X-ray crystallography using the
synchrotron at the Advanced Photon Source
at Argonne National Laboratory.
They found that CrtM performs a two-step
reaction, individually removing two
diphosphate groups from the substrate. The
substrate switches between two active sites
within the enzyme as the reaction
progresses. The most effective inhibitors
bind to both sites, blocking the enzyme
from any action.
“The leads that people have been
developing for treating these diseases really
haven ’t had any structural basis,” said
Oldfield, also a professor of Biophysics. “But
now that we can see how the protein
works, we ’re in a much better position to
design molecules that will be much more
effective against staph infections and
parasitic diseases, and potentially, in
cholesterol-lowering. ”