New compound makes drug-resistant bacteria susceptible

New compound makes drug-resistant bacteria susceptible

3:54 AM, 2nd December 2011
New compound makes drug-resistant bacteria susceptible
Jason Sello, assistant professor of chemistry, Brown University

RHOD ISLAND, US: Old antibiotics Bacteria can use efflux pumps to rid themselves of antibiotics, becoming drug-resistant until newer antibiotics are developed. By blocking those pumps, researchers can restore the potency of old antibiotics to which bacteria have become resistant.

Chemists at Brown University have synthesized a new compound that makes drug-resistant bacteria susceptible again to antibiotics. The compound - BU-005 - blocks pumps that a bacterium employs to expel an antibacterial agent called chloramphenicol. The team used a new and highly efficient method for the synthesis of BU-005 and other C-capped dipeptides.

The efflux pumps are proteins located in the membranes of bacteria that can recognize and expel drugs that have breached the membranes.

“This turns out to be a real problem in clinical settings, especially when a bacterial pathogen acquires a gene encoding an efflux pumps that acts on multiple antibiotics,” said Jason Sello, assistant professor of chemistry, Brown University. “In the worst case scenario, a bacterium can go from being drug-susceptible to resistant to five or six different drugs by acquiring a single gene.”

Until the discovery, C-capped dipeptides were known to work only against an efflux pump family associated with Gram-negative bacteria.

“If drug efflux pumps are inhibited, then bacteria will be susceptible to drugs again,” said Sello. “This approach is of interest because one would have to discover efflux pump inhibitors rather than entirely new kinds of antibacterial drugs.”

The Brown team thought that new and perhaps more potent C-capped dipeptide efflux pump blockers could be discovered. Since it is not possible to predict which C-capped dipeptides would be efflux pump blockers, they synthesized a collection of structurally diverse C-capped dipeptides and screened it for compounds with new or enhanced activities.

Normally, this is a four- to five-step process. Sello’s group reduced that to two steps, taking advantage of a technique used in other chemistry practices, known as the Ugi reaction. Using this approach, the team was able to prepare dozens of different C-capped dipeptides. They assessed each compound’s ability to block two efflux pumps in the bacterium Streptomyces coelicolor, a relative of the human pathogen Mycobacterium tuberculosis and which resists chloramphenicol, one of the oldest antibacterial drugs.

From a collection of nearly 100 C-capped dipeptides that they prepared and tested, the group discovered BU-005. The new compound excited the researchers because it prevented the MFS efflux pump family from expelling chloramphenicol. Until now, structurally related C-capped dipeptides had only been reported to prevent chloramphenicol expulsion by other drug efflux pump families.

“Our findings that C-capped dipeptides inhibit efflux pumps in both Gram-positive and Gram-negative bacteria should reinvigorate interest in these compounds," Sello said. "Moreover, our simplified synthetic route should make the medicinal chemistry on this class of compounds much simpler.”

 

© University of Brown News

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