Chemical synthesis can produce more potent antibiotics: Study

Antibiotics can be modified by a new chemical reaction making them more efficacious against drug-resistant infections, according to the research conducted by Massachusetts Institute of Technology.

By chemically linking the antibiotic vancomycin to an antimicrobial
peptide, the researchers were able to dramatically enhance the drug’s
effectiveness against two strains of drug-resistant bacteria. This kind
of modification is simple to perform and could be used to create
additional combinations of antibiotics and peptides, the researchers

‘Patients are advised to use right dose antibiotics at the right time to prevent the emergence of dangerous resistant infections.’
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“Typically, a lot of steps would be needed to get vancomycin in a
form that would allow you to attach it to something else, but we don’t
have to do anything to the drug,” says Brad Pentelute, an MIT associate
professor of chemistry and the study’s senior author. “We just mix them
together and we get a conjugation reaction.”

This strategy could also be used to modify other types of drugs,
including cancer drugs, Pentelute says. Attaching such drugs to an
antibody or another targeting protein could make it easier for the drugs
to reach their intended destinations.

Pentelute’s lab worked with Stephen Buchwald, the Camille Dreyfus
Professor of Chemistry at MIT; Scott Miller, a professor of chemistry at
Yale University; and researchers at Visterra, a local biotech company,
on the paper, which appears in the Novemeber issue of Nature Chemistry. The paper’s lead authors are former MIT postdoc Daniel Cohen, MIT postdoc Chi Zhang, and MIT graduate student Colin Fadzen.

A simple reaction

Several years ago, Cohen made the serendipitous discovery that an
amino acid called selenocysteine can spontaneously react with complex
natural compounds without the need for a metal catalyst. Cohen found
that when he mixed electron-deficient selenocysteine with the antibiotic
vancomycin, the selenocysteine attached itself to a particular spot —
an electron-rich ring of carbon atoms within the vancomycin molecule.

This led the researchers to try using selenocysteine as a “handle”
that could be used to link peptides and small-molecule drugs. They
incorporated selenocysteine into naturally occurring antimicrobial
peptides — small proteins that most organisms produce as part of their
immune defenses.

Selenocysteine, a naturally occurring amino acid that
includes an atom of selenium, is not as common as the other 20 amino
acids but is found in a handful of enzymes in humans and other

The researchers found that not only were these peptides able to link
up with vancomycin, but the chemical bonds consistently occurred at the
same location, so all of the resulting molecules were identical.
Creating such a pure product is difficult with existing methods for
linking complex molecules.

Furthermore, doing this kind of reaction with
previously existing methods would likely require 10 to 15 steps just to
chemically modify vancomycin in a way that would allow it to react with
a peptide, the researchers say.

“That’s the beauty of this method,” Zhang says. “These complex
molecules intrinsically possess regions that can be harnessed to
conjugate to our protein, if the protein possesses the selenocysteine
handle that we developed. It can greatly simplify the process.”

The researchers tested conjugates of vancomycin and a variety of
antimicrobial peptides (AMPs). They found that one of these molecules, a
combination of vancomycin and the AMP dermaseptin, was five times more
powerful than vancomycin alone against a strain of bacteria called E.

Vancomycin linked to an AMP called RP-1 was able to kill the
bacterium A. baumannii, even though vancomycin alone has no effect on
this strain. Both of these strains have high levels of drug resistance
and often cause infections acquired in hospitals.

Modified drugs

This approach should work for linking peptides to any complex
organic molecule that has the right kind of electron-rich ring, the
researchers say. They have tested their method with about 30 other
molecules, including serotonin and resveratrol, and found that they
could be easily joined to peptides containing selenocysteine.

researchers have not yet explored how these modifications might affect
the drugs’ activity.In addition to modifying antibiotics, as they did in this study, the
researchers believe they could use this technique for creating targeted
cancer drugs.

Scientists could use this approach to attach antibodies
or other proteins to cancer drugs, helping the drugs to reach their
destination without causing side effects in healthy tissue.

Adding selenocysteine to small peptides is a fairly straightforward
process, the researchers say, but they are now working on adapting the
method so that it can be used for larger proteins. They are also
experimenting with the possibility of performing this type of
conjugation reaction using the more common amino acid cysteine as a
handle instead of selenocysteine.

The research was funded by the National Institutes of Health, a
Damon Runyon Cancer Research Foundation Award, and a Sontag
Distinguished Scientist Award.

Source: Eurekalert