North­eastern Uni­ver­sity was awarded a $2.7 mil­lion grant by the National Insti­tutes of Health to help develop a tar­geted therapy to combat a con­ta­gious and poten­tially lethal bac­te­rial pathogen com­monly found in hos­pital and nursing home set­tings called Clostridium dif­fi­cile (C. dif­fi­cile). The five-​​year inter­na­tional project, led by Northeastern’s Antimi­cro­bial Center under the direc­tion of pro­fessor Kim Lewis, Ph.D., aims to create a com­bi­na­tion therapy method for humans by dis­abling the resis­tance mech­a­nisms for the nat­ural antimi­cro­bial berberine.

Our goal is to emu­late a nat­ural occur­ring process in plants that kills bac­te­rial infec­tions in humans so that we can more effec­tively treat people infected by this pathogen,” said Lewis.

Infec­tion from C. dif­fi­cile is a rising health problem, affecting more than 250,000 Amer­i­cans a year. Found in the human intes­tine in small amounts, C. dif­fi­cile can over­grow in response to antibi­otics resulting in severe intestinal dis­com­fort, col­itis, and even death, under­scoring the need for effec­tive treatments.

Pre­vious research in plants has shown that berberine, a prin­cipal com­po­nent of the plant Gold­enseal, has lim­ited antimi­cro­bial activity because Multi-​​drug Resis­tant pumps (MDRp) imme­di­ately pump berberine out of the cell. This is the only known resis­tance mech­a­nism against berberine. When MDRp inhibitors are present, how­ever, the activity of berberine against gram-​​positive bac­teria, like C. dif­fi­cile, increases by 60-​​fold. Hence this com­bi­na­tion of MDR efflux inhibitors and berberine results in a pow­erful antimi­cro­bial agent capable of erad­i­cating C. dif­fi­cile.

Many cur­rent antimi­cro­bial agents fail because bac­teria can develop a resis­tance to the agent,” said Lewis. “Given the amount of com­pounds that we can use to develop dif­ferent MDR inhibitors, our method will help us stay ahead of the pathogen resistance.”

Cur­rent treat­ment methods are only effec­tive against growing bac­teria, whereas this com­bi­na­tion method would pre­vent sta­tionary C. dif­fi­cile cells from forming spores, pre­venting a relapse.

In addi­tion, MDR inhibitors have a high prob­a­bility of being iden­ti­fied in com­pound libraries, cre­ating an oppor­tu­nity to ratio­nally manage drug resistance.

In order to elim­i­nate com­pounds that could be toxic and not func­tion in vivo, the team will use a pre­vi­ously estab­lished model to rapidly iden­tify the right com­pounds to pump into their drug devel­op­ment pipeline.

This project will be done in col­lab­o­ra­tion with Fred Ausubel, pro­fessor of genetics at Har­vard Med­ical School and mol­e­c­ular biol­o­gist at Mass­a­chu­setts Gen­eral Hos­pital, and John Bremner, pro­fessor of chem­istry at the Uni­ver­sity of Wol­lon­gong in Australia.