A
team of scientists from around the world, including from Trinity College
Dublin, has obtained high-resolution structural insights into a key bacterial enzyme,
which may help chemists design new drugs to inhibit it, thereby inhibiting
disease-causing bacteria. Their work is important amid growing concerns about
rising antibiotic resistance.
The
scientists, led by Martin Caffrey, Emeritus Fellow of Trinity's Faculty of
Medicine and School of Biochemistry and Immunology, used next-generation x-ray
crystallography and single-particle cryo-electron microscopy to "see
what's going on under the bacterial cap.", and produced a molecular
blueprint of the full-length enzyme that can be used to design drugs that
attack any structural defect.
Because
the Lnt enzyme is not found in humans. It only presents in bacteria and helps
them build stable cell membranes through which substances move in and out of
cells. It has huge potential as a therapeutic target, since any drug tailored
to it should cause fewer side effects for patients.
The
study has just been published in Science Advances.
Martin
Caffrey said: "Many disease-causing bacteria have become resistant to a
number of the drugs of choice used to treat them, and with antimicrobial
resistance generally on the rise, the World Health Organization has been
advising for some time that the post-antibiotic era coming soon, in an age
where minor injuries and common infections can be fatal."
"Therefore,
new drugs are urgently needed, and while it may be a long journey from
providing such a structural blueprint to developing new drugs, we have
addressed this potential target with precision, drawing some 'bulls-eyes' on
this target."
Background reading
What
is X-ray Crystallography?
X-ray crystallography is a scientific method used to determine
the arrangement of atoms of a crystalline solid in three-dimensional space.
X-ray crystallography is currently the most popular method for determining the
structural properties of proteins and other macromolecules. Obtaining single
crystals of the target protein is required for a successful X-ray crystallographic
application.
Presently,
nearly 90% of the proteins that have been resolved by X-ray crystallography are
represented in the more than 120,000 protein structures that have been
deposited in the protein databank. This indicates the dominance of X-ray
crystallography in structural determination.
Advantages and disadvantages of X ray
crystallography
X-ray
crystallography has some benefits, such as the fact that it is generally
inexpensive and straightforward and offers a two-dimensional view that indicates
the three-dimensional structure of a material. It produces high atomic
resolution and is not constrained by the protein's molecular weight.
But
there are some drawbacks as well. It has the drawback of requiring a
crystalline sample, which can be challenging to acquire. Another drawback is
that it might be challenging to identify the phases of the diffracted X-rays.
X
ray crystallography vs cryo-EM
Cryo-EM
and X-ray crystallography are two methods for figuring out how proteins are
structured. X-ray crystallography can produce extremely high resolutions, but
in recent years, cryo-EM has produced results that are comparable. It can be
challenging to crystallize membrane proteins, complexes, and large structures.
Therefore, Cryo-EMmight be a simpler choice. Comparatively less protein is needed for cryo-EM
than for x-ray crystallography. Samples with a yield of less than 2 mg protein
(5–10 mg/ml) may benefit from this method. In terms of sample quality and
quantity, cryo-EM is more tolerant than X-ray crystallography.
The Wall