Kim Lewis

New research opens the door for treatment of relapsing bacterial infections

by Thea Singer

It’s one thing to grow bac­teria in a test tube, per­form a screen in the lab, and find a muta­tion in the pathogen’s genes. It’s a whole other thing, and much rarer, to find the exact same muta­tion in nature—in this case, in E. coli in urine sam­ples from some 500 patients suf­fering from relapsing uri­nary tract infections.

The con­fluent dis­covery, by Uni­ver­sity Dis­tin­guished Pro­fessor Kim Lewis and his col­leagues, was pub­lished on Wednesday in the journal Nature. It could put people with relapsing UTIs on the fast track for a new ther­a­peutic reg­imen that Lewis described in an ear­lier paper.

We took a large col­lec­tion of E. coli iso­lates from patients with relapsing UTIs,” explains Lewis, who is director of the Antimi­cro­bial Dis­covery Center. “And we found that quite a number of those iso­lates had exactly the same mutation—in a gene called hipA—that we and other sci­en­tists have seen in test-​​tube experiments.”

She was delighted by what she saw: hipA leapt to the fore in both populations.Pooja Balani, a doc­toral stu­dent in Lewis’ lab at the time of the study and a first author of the paper, spent count­less hours per­forming a genetic screen with then North­eastern research assis­tant pro­fessor Marin Vulić and poring over both test-​​tube cul­tures of E. coli and patients’ UTI iso­lates, in search of hipA mutations.

The “per­sister” breakthrough

An esti­mated 150 mil­lion UTIs occur each year world­wide, accounting for $6 bil­lion in health­care costs, according to the Amer­ican Uro­log­ical Asso­ci­a­tion. The bac­terium E. coli is respon­sible for the majority of them. Antibi­otics are the stan­dard treat­ment, but often the infec­tion returns when treat­ment is stopped.

Lewis’ lab had spent years trying to learn why, and in 2001 pub­lished a paper that brought the answer into the light of day: A sub­pop­u­la­tion of bac­te­rial cells called “per­sis­ters” was con­fer­ring antibi­otic “tolerance.”

Antibi­otic tol­er­ance is dis­tinct from antibi­otic “resis­tance,” which occurs when a pathogen acquires a genetic muta­tion that allows it to code for a pro­tein that destroys the antibi­otic. Think of it this way: With resis­tance, the bac­teria bran­dish a new killer weapon. With tol­er­ance, the bac­teria hide in a fox­hole, waiting till the enemy has fled. Then they come out and multiply.

Bac­teria are one-​​cell organ­isms. To repro­duce, they simply divide: One cell becomes two cells, and so on, until an army of progeny infect the host—here, a person’s uri­nary tract. But some­times the divi­sion results in one active bac­teria cell, which con­tinues to grow and divide, and one that is alive but stops growing—it is dor­mant, existing in what Lewis calls “a spore­like state.” That is a per­sister cell.

There’s a small sub­pop­u­la­tion of per­sis­ters that are formed by all pathogens we’ve studied so far,” says Lewis. Because antibi­otics attack only actively func­tioning bac­te­rial cells, he says, per­sis­ters escape the onslaught.

Per­sis­ters are like a bet-​​hedging defense strategy for bac­teria,” says Balani. “Ulti­mately they save the population.”

From the lab to the bedside

Col­lab­o­ra­tors in the new study included Maria A. Schu­macher, Richard G. Brennan, and their stu­dents at Duke Uni­ver­sity School of Med­i­cine, who ana­lyzed the struc­ture of hipA to deter­mine how the muta­tion increased pro­duc­tion of per­sister cells. What they found was a mol­e­c­ular bal­ancing act gone awry.

The hipA gene codes for a protein—a toxin. The toxin is usu­ally held in check by another pro­tein, an anti­toxin, that is coded for by another gene, hipB. Toxin-​​antitoxin gene pairs are “scat­tered around the chro­mo­somes of all bac­teria we know of,” says Lewis. A muta­tion in either gene, how­ever, can throw the bal­ance off kilter. Hence, the more toxin pro­duced by hipA, the more likely the cell will shut down—that is, become a per­sister. “The hipA muta­tion gives rise to about 1,000 times more per­sis­ters than a gene without it,” says Lewis.

Knowing this genetic mech­a­nism could enable clin­i­cians to cus­tomize treat­ment for relapsing UTIs. “You can track whether your patient has E. coli with a hipA muta­tion, and if so, intro­duce a pulse-​​dosing reg­imen,” says Lewis, citing his ear­lier paper about pulse dosing and the pathogen that causes Lyme disease.

Pulse dosing, he says, is straight­for­ward: You give the patient an antibi­otic and it kills all the growing cells. Then the per­sister cells start “waking up.” But before they can divide to form a new pop­u­la­tion, you hit them with the antibi­otic again.

In a test tube, if you repeat this a couple of times, you can com­pletely erad­i­cate the pop­u­la­tion,” Lewis says. “I believe that the same thing can be done in people.”

Originally published in news@Northeastern on July 29, 2015.

Kim Lewis

University Distinguished Professor Kim Lewis

College of Science
Featured Faculty