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Researchers investigate four promising new treatments for Lyme disease

March 29, 2016

The ticks that transmit Lyme dis­ease have mul­ti­plied aggres­sively over the past 20 years, and now thrive in half of all coun­ties in the U.S., according to a recent study in the Journal of Med­ical Entomology.

So it's no sur­prise that when North­eastern researchers reported last May how the bac­terium that causes the dis­ease evades antibi­otics, sug­gesting new treat­ments, the media and the gen­eral public took notice.

Uni­ver­sity Dis­tin­guished Pro­fessor Kim Lewis, who leads the Lyme dis­ease research team, is now expanding that ther­a­peutic reach with the help of a $1.5 mil­lion grant from the Steven and Alexandra Cohen Foundation.

The team is pur­suing four arms of treatment-related research at Northeastern's Antimi­cro­bial Dis­covery Center, which Lewis directs.

They are: a mouse study of a reg­imen that erad­i­cated the bac­terium in the test tube, set­ting the stage for human trials; antibi­otic cock­tails using existing drugs; strate­gies to dis­cover new drugs that selec­tively target the Lyme bac­terium; and ways to alter the com­po­si­tion of the microbiome--the com­mu­nity of microor­gan­isms inhab­iting the human body--to stop the autoim­mune reac­tions that char­ac­terize the disease.

All four show exciting promise. The grant, Lewis says, "will give us the flex­i­bility to test our approaches in par­allel, which will save us an enor­mous amount of time."

Pre­venting chronic disease

Time is of the essence. According to the Cen­ters for Dis­ease Con­trol and Pre­ven­tion, about 300,000 people are diag­nosed with Lyme dis­ease in the U.S. each year. The dis­ease is trans­mitted by ticks pri­marily car­rying the bac­terium Bor­relia burgdor­feri, though a new less preva­lent bac­te­rial species, Bor­relia may­onii, was iden­ti­fied by Mayo Clinic researchers in February.

If Lyme is caught early, patients gen­er­ally recover quickly when treated with antibi­otics, pri­marily doxy­cy­line. How­ever, 10 to 20 per­cent of patients go on to develop a debil­i­tating chronic con­di­tion called Post-Treatment Lyme Dis­ease Syn­drome, or PTLDS, with symp­toms that include extreme fatigue, arthritis, muscle pain, and cog­ni­tive difficulties.

"I find it amazing that when you show up at the doctor's office you are not told that there is a 10 to 20 per­cent chance that your life as you know it has ended," says Lewis. "Nobody seems to be focusing on the next step: How to pre­vent the sub­se­quent rise of the chronic condition."

A new regimen

Lewis and his col­leagues are pro­viding that focus. A sub­pop­u­la­tion of B. burgdor­feri cells, they dis­cov­ered ear­lier, are "per­sister" cells--they are alive but lie dor­mant, in a spore­like state. Because antibi­otics attack only actively func­tioning bac­te­rial cells, per­sis­ters escape the onslaught. How­ever, once the antibi­otic has been flushed from the system, the per­sis­ters "wake up," says Lewis, dividing and mul­ti­plying until an army of progeny infect the host.

That's where "pulse dosing" comes in. Lewis' team, in col­lab­o­ra­tion with researchers studying B. burgdor­feri in mice at Tufts University's Sackler School of Bio­med­ical Sci­ences, has been ana­lyzing the effect of giving the mice an antibi­otic that kills all the actively func­tioning bac­te­rial cells and then--using the timing that erad­i­cated the pathogen in the test tube--giving addi­tional doses to quash the per­sister cells as they begin to wake up but before they reproduce.

Plans are in the works for the first pulse-dosing human trials with med­ical schools.

Drugs com­bined and discovered

Doxy­cy­cline may be stan­dard first-line treat­ment for Lyme, but, says Lewis, it doesn't even kill B. burgdor­feri, it just sup­presses its growth, leaving the rest of the work to the immune system. "We simply asked the ques­tion: 'Is it pos­sible to com­bine existing antibi­otics to treat not only chronic Lyme but any stage of Lyme if the diag­nosis is unambiguous"

The researchers have already found com­bi­na­tions that are effec­tive against the B. burgdor­feri in the test tube and will move on to animal studies next.

They are tack­ling new-drug dis­covery on two fronts: Plumbing the 200,000-plus com­pounds in their col­lec­tion at North­eastern to find the ones that act solely against B. burgdor­feri to avoid unwanted side effects and, in col­lab­o­ra­tion with Novo­bi­otic Phar­ma­ceu­ti­cals, extracting drugs from bac­teria that live in soil using the iChip, a device devel­oped by Slava Epstein, Dis­tin­guished Pro­fessor at North­eastern, in col­lab­o­ra­tion with Lewis. The iChip pro­vides access to the 99 per­cent of microbes in the envi­ron­ment that hereto­fore could not be grown in the lab.

"So far we have iden­ti­fied two lead com­pounds that kill B. burgdor­feri and have no activity against other bac­teria," says Lewis.

The researchers are also exploring whether the micro­biome has "shifted" in those with PTLDS, to see whether intro­ducing cer­tain microor­gan­isms might shift it back. Animal studies have shown that manip­u­lating the micro­biome com­po­si­tion alle­vi­ates symp­toms of autoim­mune dis­eases such as rheuma­toid arthritis, which share many char­ac­ter­is­tics with PTLDS.

"We are going at Lyme dis­ease with every­thing we have," says Lewis.

Northeastern University

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