Discovery may explain difficulty in treating Lyme disease

North­eastern Uni­ver­sity researchers have found that the bac­terium that causes Lyme dis­ease forms dor­mant per­sister cells, which are known to evade antibi­otics. This sig­nif­i­cant finding, they said, could help explain why it’s so dif­fi­cult to treat the infec­tion in some patients.

It hasn’t been entirely clear why it’s dif­fi­cult to treat the pathogen with antibi­otics since there has been no resis­tance reported for the causative agent of the dis­ease,” explained Uni­ver­sity Dis­tin­guished Pro­fessor Kim Lewis, who led the North­eastern research team.

In other chronic infec­tions, Lewis’ lab has tracked the resis­tance to antibi­otic therapy to the pres­ence of per­sister cells—which are drug-​​tolerant, dor­mant vari­ants of reg­ular cells. These per­sister cells are exactly what they’ve iden­ti­fied here in Bor­relia burgdor­feri, the bac­terium that causes Lyme disease.

The researchers have also reported two approaches—one of them quite promising—to erad­i­cate Lyme dis­ease, as well as poten­tially other nasty infections.

Lewis and his col­leagues pre­sented their find­ings in a paper pub­lished online last week in the journal Antimi­cro­bial Agents and Chemotherapy. He co-​​authored the paper with North­eastern doc­toral stu­dents Bijaya Sharma and Autumn Brown, both PhD’16; recent grad­uate Nicole Matluck, S’15, who received her Bach­elor of Sci­ence in Behav­ioral Neu­ro­science; and Linden T. Hu, a pro­fessor of mol­e­c­ular biology and micro­bi­ology at Tufts University.

The research was sup­ported by grants from the Lyme Research Alliance and the National Insti­tutes of Health.

Lyme dis­ease affects 300,000 people annu­ally in the U.S., according to the Cen­ters for Dis­ease Con­trol and Pre­ven­tion, and is trans­mitted to people via bites from infected black­legged ticks. If caught early, patients treated with antibi­otics usu­ally recover quickly. How­ever, about 10 to 20 per­cent of patients, par­tic­u­larly those diag­nosed later, who have received antibi­otic treat­ment may have per­sis­tent and recur­ring symp­toms including arthritis, muscle pain, fatigue, and neu­ro­log­ical prob­lems. These patients are diag­nosed with Post-​​treatment Lyme Dis­ease Syndrome.

In addi­tion to iden­ti­fying the pres­ence of these per­sister cells, Lewis’ team also pre­sented two methods for wiping out the infection—both of which were suc­cessful in lab tests. One involved an anti-​​cancer agent called Mit­o­mycin C, which com­pletely erad­i­cated all cul­tures of the bac­terium in one fell swoop. How­ever, Lewis stressed that, given Mit­o­mycin C’s tox­i­city, it isn’t a rec­om­mended option for treating Lyme dis­ease, though his team’s find­ings are useful to helping to better under­stand the disease.

The second approach, which Lewis noted is much more prac­tical, involved pulse-​​dosing an antibi­otic to elim­i­nate per­sis­ters. The researchers intro­duced the antibi­otic a first time, which killed the growing cells but not the dor­mant per­sis­ters. But once the antibi­otic washed away, the per­sis­ters woke up, and before they had time to restore their pop­u­la­tion the researchers hit them with the antibi­otic again. Four rounds of antibi­otic treat­ments com­pletely erad­i­cated the per­sis­ters in a test tube.

This is the first time, we think, that pulse-​​dosing has been pub­lished as a method for erad­i­cating the pop­u­la­tion of a pathogen with antibi­otics that don’t kill dor­mant cells,” Lewis said. “The trick to doing this is to allow the dor­mant cells to wake up.”

He added: “This gives you an idea that you could, in prin­ciple, estab­lish a sim­ilar reg­i­ment for treating patients for this and other chronic diseases.”

Lewis is a fac­ulty member in the biology depart­ment and directs Northeastern’s Antimi­cro­bial Dis­covery Center. Over the past decade he has led pio­neering work on this spe­cial­ized class of cells pro­duced by all pathogens known as per­sis­ters. Ear­lier this year, Lewis, biology pro­fessor Slava Epstein, and other col­leagues pub­lished ground­breaking researchin Nature pre­senting a new antibi­otic that kills pathogens without encoun­tering any detectable resistance.

In pre­vious work, Lewis’ lab iden­ti­fied a com­pound called ADEP that causes dor­mant per­sister cells in MRSA to self-​​destruct. This com­pound was among the first options the researchers tried out to combat Lyme dis­ease. But it didn’t work, and nei­ther did com­bi­na­tions of stan­dard antibi­otics used to treat the dis­ease. The team thought it had hit a dead end yet remained vig­i­lant in its quest to iden­tify promising alter­na­tive options.

What we came up with was the pulse-​​dosing reg­imen, which worked beau­ti­fully,” Lewis explained. “I think this could be very useful, espe­cially for antibi­otics for which resis­tance doesn’t rapidly develop.”

Though the researchers iden­ti­fied the pres­ence of these per­sister cells, they also note in their paper that the mech­a­nisms by which the per­sis­ters are able to sur­vive remain unknown. More work in this area will be required, they wrote. This is a press release that originally appeared on the Northwestern website.


Substack subscription form sign up
The material in this press release comes from the originating research organization. Content may be edited for style and length. Want more? Sign up for our daily email.