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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 have been 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 something going," says Brad Pentelute, an associate professor of MIT. 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 these drugs to an antibody or other 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, 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 MIT postdoc Daniel Cohen, MIT postdoc Chi Zhang, and MIT graduate student Colin Fadzen.
Single reaction
Several years ago, Cohen made the discovery that an amino acid salt selenocysteine can spontaneously react with complex natural compounds without the need for a metal catalyst. Cohen found that when 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.
Selenocysteine has 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 produced as part of their immune defenses. Selenocysteine, a naturally occurring amino acid that includes an atom of selenium, is not as common to other amino acids but is found in a handful of enzymes in humans and other organisms.
The researchers found that these peptides were not related to vancomycin, but the result was similar to those in the same location. Such a product is difficult with existing methods for linking complex molecules. Further, doing this kind of reaction would have required 10 to 15 steps to be made 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 are inherently capable of being conjugated to our protein, if the protein possesses the selenocysteine that we 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 AMP dermaseptin, were more easily compared to those of 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 other molecules, including serotonin and resveratrol, and found that they could be easily combined with peptides containing selenocysteine. The researchers have not yet explored these modifications.
In addition to modifying antibiotics, they have been identified in this study, the researchers believe they could use this technique. Scientists could use this approach to attach their antibodies to cancer drugs, by using the drugs to reach their destination.
Adding selenocysteine to small peptides is a fairly straightforward process, the researchers say, but they are 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.
Explore further:
Supercharged antibiotics could turn tide against superbugs
More information:
A chemoselective strategy for late-stage functionalization of complex small molecules with polypeptides and proteins, Nature Chemistry (2018). DOI: 10.1038 / s41557-018-0154-0, https://www.nature.com/articles/s41557-018-0154-0
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