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New Processes Devised to Boost Antibiotics

MRSA bacteria

Methicillin-resistant Staphylococcus aureus, or MRSA, bacteria (Defense.gov)

6 Nov. 2018. Researchers in chemistry at two institutions report new techniques that lab tests show modify current antibiotics to make them more effective against infections that resist today’s antibiotics. Separate teams from Massachusetts Institute of Technology and Stanford University in California report their findings in yesterday’s issue of the journal Nature Chemistry and the 2 November issue of  Journal of the American Chemical Society; paid subscriptions required for both papers.

The problem of antimicrobial resistance problem, notes World Health Organization is global and growing. The organization says new mechanisms of resistance to antibiotics are emerging that threaten our ability to combat infections from pneumonia, tuberculosis, blood poisoning, gonorrhea, and foodborne diseases. In addition, Centers for Disease Control and Prevention says at least 2 million people in the U.S. become infected with bacteria that are resistant to antibiotics and at least 23,000 people die each year as a direct result of these infections.

Researchers from the MIT lab of Bradley Pentelute developed a technique to enhance the power of the antibiotic vancomycin, used to treat a wide variety of bacterial infections. Some strains of Enterococci bacteria, for example, are resistant to vancomycin, causing intestinal infections, particularly in health care facilities. Pentelute worked with colleagues from MIT, Yale University, and the biotechnology company Visterra Inc. to add a peptide to the chemistry of vancomycin that overcomes resistance to the antibiotic.

Their technique uses an amino acid in the body known as selenocysteine that reacts easily with more complex compounds. In earlier research, one of the team members found selenocysteine, a natural but uncommon amino acid, could mix with vancomycin. By combining selenocysteine, the researchers could also add other natural compounds, including peptides, short chains of amino acids resembling simple proteins produced by the immune system. The peptides in this case have antimicrobial properties that can produce a stronger variation of vancomycin.

The process of conjugating the peptides to vancomycin turned out to be simpler than the researchers expected. “Typically, a lot of steps would be needed to get vancomycin in a form that would allow you to attach it to something else,” says Pentelute in an MIT statement, “but we don’t have to do anything to the drug. We just mix them together and we get a conjugation reaction.”

The technique makes it possible to combine vancomycin with several antimicrobial peptides, which they tested successfully in lab cultures with a variety of gram-positive and gram-negative bacteria.  “Gram” refers to a classification for bacteria where the microbes either retain (gram-positive) or shed (gram-negative) a test stain on their protective cell coatings.

A different peptide attachment

Stanford University researchers from the labs of chemistry professors Lynette Cegelski and Paul Wender conjugated a different technique for attaching an antimcrobial peptide compound to vancomycin. In this case, the super-charged vancomycin penetrates and destroys stubborn colonies of methicillin-resistant Staphylococcus aureus, or MRSA, bacteria known as biofilms, also a continuing problem in health care facilities.

Like the MIT team, the Stanford researchers modified vancomycin rather than design an entirely new drug.”You don’t have to invent a new drug,” says Wender in a Stanford statement. “You just have to fix the problems with existing drugs.” The peptide used by Cegelski, Wender, and colleagues to fix vancomycin is a form of octaarginine known to penetrate cells. Octaarginines can also serve as carriers of other molecules that can act on the cells after they break through the outer membranes.

Tests of their conjugated vancomycin they call V-r8 in lab cultures show V-r8 binds to MRSA bacteria for twice as long as ordinary vancomycin, killing off most of the bacterial cells. V-r8 is also 10 times more effective against MRSA biofilms than plain vancomycin, by penetrating the tough cellular communities. In addition, the researchers tested V-r8 in lab mice with MRSA infections, with V-r8 killing 97 percent of the bacteria in about 5 hours, about 6 times more effective than unmodified vancomycin.

The researchers plan to test this technique on other types of bacteria. “This was just the first effort,” notes Cegelski.

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