PUBLIC RELEASE DATE:

9-Dec-2014

Contact: Kevin Stacey kevin_stacey@brown.edu 401-863-3766 Brown University @brownuniversity

PROVIDENCE, R.I. [Brown University] -- Harmful bacteria have evolved some ingenious mechanisms to resist antibiotics. One of those is the drug efflux pump -- proteins that stand guard along bacterial cell membranes, identifying antibacterial agents that pass through the membrane and swiftly ejecting them from the cell.

"These drug efflux pumps are extremely problematic," said Jason Sello, associate professor of chemistry at Brown University. "The drugs are pumped out of the bacteria and cannot reach the critical concentration for toxicity."

Sello and a team of researchers from Brown have come up with a new strategy that may help sneak drugs past the efflux guards. The new approach makes use of molecular fragments administered alongside antimicrobial agents. The efflux pumps are kept busy pumping out the fragments while the antimicrobial agents are able to stay inside the cell.

"We're basically using decoys," Sello said. "It's a relatively simple idea to solve a significant problem in medicine."

Sello and his colleagues describe the method and some preliminary lab results in a paper published in the journal ACS Infectious Diseases. The paper was co-authored by graduate students Corey Compton and Daniel Carney and undergraduate Patrice Groomes.

For the study, Sello and his team experimented with a promising new class of antimicrobial drug candidates called acyldepsipeptides or ADEPs. The compounds have been shown to be effective in killing many species of bacterial pathogens but are generally less effective against the bacterium that causes tuberculosis. It had been reported that the ADEP resistance of M. tuberculosis was due to the presence of one or perhaps more efflux pumps. Sello and his team were seeking a way to interfere with those pumps so that the ADEPs could be used for the treatment of tuberculosis.

"There are two scenarios for how an ADEP efflux pump could operate," Sello said. "The pump could either recognize the entire molecule or some portion of it. We thought, if the latter scenario is operative, then a molecule comprising the minimal portion of the ADEP that is recognized by the pump could competitively interfere with efflux of the ADEP."

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Molecular decoys help overcome drug resistance