New treatment discovered to cure MRSA infection

The so-​​called "superbug" infects 1 mil­lion Amer­i­cans each year. A major problem with MRSA is the devel­op­ment of deep-​​seated chronic infec­tions such as osteomyelitis (bone infec­tion), endo­carditis (heart infec­tion), or infec­tions of implanted med­ical devices. Once estab­lished, these infec­tions are often incur­able, even when appro­priate antibi­otics are used.

Bac­teria such as MRSA have evolved to actively resist cer­tain antibi­otics, a fact that has gen­er­ated sig­nif­i­cant interest among the sci­en­tific and med­ical com­mu­ni­ties. But Lewis, Director of Northeastern's Antimi­cro­bial Dis­covery Center, sus­pected that a dif­ferent adap­tive func­tion of bac­teria might be the true cul­prit in making these infec­tions so devastating.

The new work rep­re­sents the cul­mi­na­tion of more than a decade of research on a spe­cial­ized class of cells pro­duced by all pathogens called per­sis­ters. According to Lewis, these cells evolved to sur­vive. "Sur­vival is their only func­tion," he said. "They don't do any­thing else."

Lewis and his research team posited that if they could kill these expert sur­vivors, per­haps they could cure chronic infections -- even those resis­tant to mul­tiple antibi­otics such as MRSA. Fur­ther­more, said Brian Conlon, a post­doc­toral researcher in Lewis' lab and first author on the paper, "if you can erad­i­cate the per­sis­ters, there's less of a chance that resis­tance will develop at all."

Lewis, who was elected to the Amer­ican Academy of Micro­bi­ology in 2011 for his schol­ar­ship in the field, has found that per­sis­ters achieve their sin­gular goal by entering a dor­mant state that makes them imper­vious to tra­di­tional antibi­otics. Since these drugs work by tar­geting active cel­lular func­tions, they are use­less against dor­mant per­sis­ters, which aren't active at all. For this reason, per­sis­ters are crit­ical to the suc­cess of chronic infec­tions and biofilms, because as soon as a treat­ment runs its course, their reawak­ening allows for the infec­tion to estab­lish itself anew.

In the recent study, which also includes con­tri­bu­tions from assis­tant pro­fessor Steve Leonard of the Depart­ment of Phar­macy Prac­tice, Lewis' team found that a drug called ADEP effec­tively wakes up the dor­mant cells and then ini­ti­ates a self-​​destruct mech­a­nism. The approach com­pletely erad­i­cated MRSA cells in a variety of lab­o­ra­tory exper­i­ments and, impor­tantly, in a mouse model of chronic MRSA infection.

Cou­pling ADEP with a tra­di­tional antibi­otic, Conlon noted, allowed the team to com­pletely destroy the bac­te­rial pop­u­la­tion without leaving any survivors.

As with all other antibi­otics, actively growing bac­te­rial cells will likely develop resis­tance to ADEP. How­ever, Lewis said, "cells that develop ADEP resis­tance become rather wimpy." That is, other tra­di­tional drugs such as rifampicin or line­zolid work well against ADEP-​​resistant cells, pro­viding a unique cock­tail that not only kills per­sis­ters but also elim­i­nates ADEP-​​resistant mutant bacteria.

Dr. Richard Novick of New York University's Lan­gone Med­ical Center and a leader in the field said the research is a "bril­liant out­growth of Kim Lewis' pio­neering work on bac­te­rial per­sis­ters and rep­re­sents a highly cre­ative ini­tia­tive in this era of dimin­ishing antibi­otic utility."

While ADEP tar­gets MRSA, Lewis' team believes sim­ilar com­pounds will be useful for treating other infec­tions as well as any other dis­ease model that can only be over­come by elim­i­nating a pop­u­la­tion of rogue cells, including can­cerous tumors. They are pur­suing sev­eral already.