Nav: Home

Chemical synthesis could produce more potent antibiotics

November 05, 2018

CAMBRIDGE, MA -- Using a novel type of chemical reaction, MIT researchers have shown that they can modify antibiotics in a way that could potentially make them more effective against drug-resistant infections.

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 say.

"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 Nov. 5 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 organisms.

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

Massachusetts Institute of Technology

Related Antibiotics Articles:

Resistance can spread even without the use of antibiotics
Antibiotic resistance does not spread only where and when antibiotics are used in large quantities, ETH researchers conclude from laboratory experiments.
Selective antibiotics following nature's example
Chemists from Konstanz develop selective agents to combat infectious diseases -- based on the structures of natural products
Antibiotics can inhibit skin lymphoma
New research from the LEO Foundation Skin Immunology Research Center at the University of Copenhagen shows, surprisingly, that antibiotics inhibit cancer in the skin in patients with rare type of lymphoma.
Antibiotics may treat endometriosis
Researchers at Washington University School of Medicine in St. Louis have found that treating mice with an antibiotic reduces the size of lesions caused by endometriosis.
How antibiotics help spread resistance
Bacteria can become insensitive to antibiotics by picking up resistance genes from the environment.
Overuse of antibiotics not what the doctor ordered
With increased use of antibiotics worldwide linked to growing antibiotic resistance, a world-first study co-authored by a QUT researcher has highlighted the growing impact of non-prescription supply of antibiotics in community pharmacies, and the urgent need for better enforcement of laws.
Bacterial armor could be a new target for antibiotics
Boosting efforts to fight antibiotic resistance, Stanford researchers have found that a thin membrane, thought to be just a shrink wrap around some bacterial cell walls, has structural properties critical for survival.
Combining antibiotics changes their effectiveness
The effectiveness of antibiotics can be altered by combining them with each other, non-antibiotic drugs or even with food additives.
Perception that antibiotics are harmless is widespread
A new study of decision-making about the use of antibiotics in medicine has found that the mistaken belief that antibiotics are harmless is widespread, especially among patients.
Complementing conventional antibiotics
Antimicrobial resistance (AMR) is a major medical problem worldwide, impacting both human health and economic well-being.
More Antibiotics News and Antibiotics Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#538 Nobels and Astrophysics
This week we start with this year's physics Nobel Prize awarded to Jim Peebles, Michel Mayor, and Didier Queloz and finish with a discussion of the Nobel Prizes as a way to award and highlight important science. Are they still relevant? When science breakthroughs are built on the backs of hundreds -- and sometimes thousands -- of people's hard work, how do you pick just three to highlight? Join host Rachelle Saunders and astrophysicist, author, and science communicator Ethan Siegel for their chat about astrophysics and Nobel Prizes.