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Biological Chemistry

Disarming Superbugs With The Aid Of A Glycolipid Gladiator

Medicinal Chemistry: Researchers synthesize new agents that could help restore the potency of antibiotics

by Deirdre Lockwood
June 17, 2015

SHOT IN THE ARM
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Credit: ACS Med. Chem. Lett.
A triazole-linked glycolipid made with a click-chemistry reaction restores the potency of existing antibiotics against methicillin-resistant Staphylococcus aureus. The triazole ring (red) plays a crucial role in its effectiveness as an adjuvant.
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Credit: ACS Med. Chem. Lett.
A triazole-linked glycolipid made with a click-chemistry reaction restores the potency of existing antibiotics against methicillin-resistant Staphylococcus aureus. The triazole ring (red) plays a crucial role in its effectiveness as an adjuvant.

Methicillin-resistant Staphylococcus aureus (MRSA) causes more than 75,000 infections per year in the U.S. In 2011, it had a 14% fatality rate, according to the Centers for Disease Control & Prevention. Researchers have struggled to develop new antibiotics that can outwit these superbugs, which resist nearly all of the β-lactam antibiotics—the most widely used antibiotic family, which includes methicillin.

So some scientists have pursued a different strategy: developing adjuvants that restore the potency of antibiotics, allowing them once again to knock out their targets. Now researchers have synthesized a new class of these compounds, a set of glycolipids (ACS Med. Chem. Lett. 2015, DOI: 10.1021/acsmedchemlett.5b00142).

Daijie Chen of China State Institute of Pharmaceutical Industry, Xiao-Peng He of East China University of Science & Technology, and their colleagues used a rapid and efficient click-chemistry reaction to make 21 glycolipid derivatives by coupling one of three sugar azides to one of seven alkynyl lipids with various lengths of carbon chains. Then they measured the concentration of the β-lactam antibiotic oxacillin that was required to inhibit MRSA growth, with or without the addition of individual glycolipids. Five of the glycolipids lowered this inhibitory concentration by 93.6 to 99.6%. The most promising one, a triazolyl glucoside paired with a 12-carbon lipid, showed similar activity when tested with several other β-lactam antibiotics.

The researchers hypothesize that the adjuvant may work by suppressing MRSA’s expression of a protein that disrupts the ability of β-lactam antibiotics to interfere with bacterial cell wall synthesis. They found that treating MRSA with both oxacillin and glycolipid lowered expression of the gene encoding the protein, compared with oxacillin treatment alone.

The scientists also determined that the triazole ring of the glycolipids was essential for their activity because a derivative made without the ring was a much weaker adjuvant. The ring facilitates the formation of micelles, which could encapsulate the antibiotic and help carry the drug to the bacteria, Chen and He say.

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