– Bonnie Crater, founder and vice-chair of the Board of Directors, Bay Area Lyme Foundation
What does an anti-alcoholism drug have to do with Lyme disease? Nothing—until a 2016 study funded by Bay Area Lyme Foundation found a link. From around 2014 through 2017, two labs on opposite coasts—one at Johns Hopkins University and one at Stanford—were testing thousands of FDA-approved drugs to identify an existing drug that worked against “persister” forms of Borrelia burgdorferi (Bb), the bacteria that causes Lyme disease(1,2,3,4). Why were they doing this?
Here’s a little background. Borrelia burgdorferi, a spirochete, when cultured in a lab has roughly 3 different forms: a) a culture with predominantly long or corkscrew forms, b) a culture with predominantly round forms and some microcolonies, and c) a culture with predominantly microcolonies (2). Most laboratory studies regarding the effectiveness of antibiotics are conducted in cultures on long forms. In this long form, the spirochete is motile and can divide (although very slowly) and consequently, some antibiotics work much better on the long form. However, after exposure to antibiotics such as doxycycline, the spirochete curls up into a round form and some clump together with other spirochetes to form a few microcolonies. These round-body and microcolony forms are understood to be a defensive posture for the bacteria.
For patients who have the chronic form of Lyme disease, it is hypothesized for the purposes of finding better antibiotics that these patients have persister forms of the bacteria. Dr. Kim Lewis, research professor at Northeastern University published his paper in 2015 and stated matter-of-factly Borrelia burgdorferi, the Causative Agent of Lyme Disease, Forms Drug-Tolerant Persister Cells. And while Dr. Lewis’s work is in the lab (and not on animals or humans), his work has been corroborated by others who found persister Borrelia in mice, dogs, primates, and humans (6-11). In addition, it is widely known that inflammation is a big challenge for chronic Lyme patients which makes them feel poorly overall and have chronic pain symptoms. Consequently, Bay Area Lyme Foundation’s search for new treatments for chronic Lyme conditions included the ability to eliminate all forms of Bb as well as to reduce chronic inflammation associated with Lyme disease.
The exploration of FDA-approved drugs as a Lyme therapeutic is a key strategy for Bay Area Lyme Foundation on our mission “to make Lyme disease easy to diagnose and simple to cure.” Our approach for the last five years has been pretty straightforward: (1) identify borreliacidal drugs in vitro (translation—drugs that kill Bb in a lab), (2) pick the winners and put them into mouse studies and (3) pick the mouse study winners and put them into a clinical trial.
Could we find drugs used for other purposes that kill Borrelia and reduce inflammation? We didn’t know. But Dr. Jayakumar Rajadas, director of Stanford University’s BioADD lab, was on a mission. Dr. Rajadas’s empathy for Lyme patients was notable and he was determined to see if any in a library of FDA-approved drugs would kill long and persister forms of Borrelia and help patients feel better by eliminating the infection and reducing inflammation.
In Dr. Rajadas’s 2016 laboratory study, Identification of New Drug Candidates Against Borrelia burgdorferi using high-throughput screening, post-doctoral researcher Venkata Raveendra Pothineni dedicated himself to the task of running a set of tests on 4,366 FDA-approved compounds. Of the over 4000 drugs screened for activity against Bb, Tetraethylthiuram disulfide was the top candidate. Tetraethylthiuram disulfide, also known as disulfiram and branded Antabuse, is an anti-alcoholism treatment that literally makes a patient have a massive hangover if he or she drinks any alcohol. Disulfiram is known to also have antibiotic properties. (5)
After reading Dr. Rajadas’s 2016 high-throughput screening paper, Dr. Kim Lewis became very curious about disulfiram and ran his own tests with some very interesting results. In October of 2016, Dr. Lewis presented his lab’s work as part of a keynote speech for the Mount Sinai School of Medicine 1st Annual Symposium: Lyme Disease in the Era of Precision Medicine which was sponsored by the Steven & Alexandra Cohen Foundation in New York City. During that speech, Dr. Lewis mentioned the work of Dr. Rajadas’s group showing that disulfiram was a very potent agent against Borrelia burgdorferi persisters. A video recording of Dr. Lewis’s keynote was placed on YouTube. Sometime after that, a patient of Dr. Ken Liegner, who had been following Dr. Lewis’s work, discovered the YouTube video recording of Dr. Lewis’s speech. This individual, an engineer, was doing fairly well on intensive anti-microbial treatment for both Lyme disease and babesiosis but whenever treatment was suspended, he deteriorated with returning symptoms. Like many Lyme patients, the engineer combed the internet for improved methods of treatment that could keep him well.
After finding the YouTube video and bringing it to Dr. Liegner’s attention, the engineer requested Dr. Liegner to start a treatment with disulfiram. The engineer has remained clinically well without need for further treatment for more than two years. Dr. Liegner, who read the publication by Drs. Pothineni and Rajadas which was the basis of Dr. Lewis’s comments, contacted Dr. Rajadas to learn more about his work. After treating several patients with disulfiram, Dr. Liegner published a case series in May 2019 which described his experiences with use of this drug. While not every patient has had as dramatically favorable an outcome as the engineer, Dr. Liegner remains very impressed by the utility of disulfiram and has not seen such dramatic results with the application of any other agent during his 30 years of practice in treating individuals suffering from chronic Lyme disease and chronic babesiosis.
Since then, other physicians have started prescribing disulfiram for patients, including Dr. Richard Horowitz of Hyde Park, New York. In addition, Bay Area Lyme Foundation funded a mouse study with Dr. Monica Embers at Tulane University, Dr. Brian Fallon of Columbia University has initiated a pilot clinical trial, and Dr. Rajadas has continued his work to identify an improved formulation for disulfiram and worked to demonstrate borreliacidal and anti-inflammatory activity in mice. In addition, several Facebook groups have formed for patients are sharing their experience with disulfiram.
While the effectiveness of disulfiram has not yet been evaluated by formal clinical trials and the exact mechanisms by which it exerts its effects on Borrelia is still in the early days of discovery, we know at least some chronic Lyme patients seem to be benefiting from its use. I think we can all be grateful for that. The story of disulfiram is also a story of collaboration across physicians, scientists, foundations, and patients, who are all seeking a cure for Lyme disease. And let the scientists and clinicians continue to collaborate carrying on this important work, while the rest of us cross our fingers that maybe we have gotten lucky and we’ve found a solid treatment that is inexpensive, oral, and relatively safe for chronic Lyme disease.
As a final word, we are not physicians or clinicians at Bay Area Lyme Foundation. If you are a tick-borne disease patient interested in disulfiram, please consult your healthcare provider for further information.
DRUG SCREENINGS REFERENCES:
(1) Feng J, Wang T, Shi W, Zhang S, Sullivan D, Auwaerter PG, Zhang Y. Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library. Emerg Microbes Infect. 2014 Jul;3(7):e49.
(2) Feng J, Auwaerter PG, Zhang Y. Drug combinations against Borrelia burgdorferi persisters in vitro: eradication achieved by using daptomycin, cefoperazone and doxycycline. PLoS One. 2015 Mar 25;10(3):e0117207
(3) Rajadas J. Identification of new drug candidates against Borrelia burgdorferi using high throughput screening, Dovepress 1April 2016: Vol 2016:10 p1307-1322
(4) Pothineni VR, Wagh D, Babar MM, Inayathullah M, Watts RE, Kim KM, Parekh MB, Gurjarpadhye AA, Solow-Cordero D, Tayebi L, Rajadas J. Screening of NCI-DTP library to identify new drug candidates for Borrelia Burgdorferi. J Antibiot (Tokyo). 2017 Mar;70(3):308-312.
(5) Long TE. Repurposing Thiram and Disulfiram as Antibacterial Agents for Multidrug-Resistant Staphylococcus aureus Infections. Antimicrob Agents Chemother. 2017 Aug 24;61(9). pii: e00898-17.
ANIMAL STUDIES REFERENCES:
(6) Barthold SW, Hodzic E, Imai DM, Feng S, Yang X, Luft BJ. Ineffectiveness of tigecycline against persistent Borrelia burgdorferi. Antimicrob Agents Chemother.2010;54(2):643-651.
(7) Hodzic E, Feng S, Holden K, Freet KJ, Barthold SW. Persistence of Borrelia burgdorferi following –
(8) antibiotic treatment in mice. Antimicrob Agents Chemother. 2008;52:1728-1736.
(9) Straubinger RK, Summers BA, Chang YF, Appel MJ. Persistence of Borrelia burdorferi in experimentally infected dogs after antibiotic treatment. J Clin Micobiol. 1997;35(1):111-116.
(10) Embers ME, Hasenkampf NR, Jacobs MB, Tardo AC Doyle-Meyers LA, Philipp MT, Hodzic E. Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding. PLoS One. 2017; 12(12):e189071.
(11) Nocton JJ, Dressler F, Rutledge BJ, Rys PN, Persing DH, Steere AC. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid from patients with Lyme arthritis. N Eng J Med.1994;330:229-234.
(12) Lawrence C, Lipton RB, Lowy FD, Coyle PK. Seronegative chronic relapsing neuroborreliosis. Eur Neurol. 1995;35(2)113-7.
(13) Chancellor M, McGinnis P, Kilholma P, Hirsch I. Urinary dysfunction in Lyme disease. J of Urol. 1993;149(1):26-30.
DISULFIRAM, CLINICAL APPLICATION FOR LYME DISEASE, REFERENCES
(14) Liegner, Kenneth B. (May 2019). “Disulfiram (Tetraethylthiuram Disulfide) in the Treatment of Lyme Disease and Babesiosis: Report of Experience in Three Cases”. Antibiotics. 8 (2): 72. doi:10.3390/antibiotics8020072