Interview with Prof. Ying Zhang at the NorVect Conference 2015
Prof Ying Zhang from John Hopkins Bloomberg School of Public Health explains why Lyme disease is so difficult to treat. Having worked with Tuberculosis (TB) for many years, he sees the similarities and differences between these to bacteria. With Tuberculosis it is known that you have to treat with certain drug combinations that kill the growing form and the non-growing form (persisters) and if you treat shorter than 6 months, the patient will get a relapse.
The bacterium that causes Lyme disease is much more advanced than the TB bacterium, and the main reason is that it also takes a persisting form. These persister forms of the Borrelia bacteria cannot be cultured.
The two views – ILADS and IDSA are two different ways of seeing the same disease. Prof. Zhang thinks they are both right. When it comes to acute Lyme disease, IDSA is right. Then you only need shorter courses of treatment. When the disease turns chronic, longer courses of treatment with the right drug combinations are needed (ILADS view).
Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library Jie Feng, Ting Wang, Wanliang Shi, Shuo Zhang, David Sullivan, Paul G Auwaerter and Ying Zhang Published online 2 July 2014
from abstract – ‘We identified 165 agents approved for use in other disease conditions that had more activity than doxycycline and amoxicillin against B. burgdorferi persisters. The top 27 drug candidates from the 165 hits were confirmed to have higher anti-persister activity than the current frontline antibiotics. Among the top 27 confirmed drug candidates from the 165 hits, daptomycin, clofazimine, carbomycin, sulfa drugs (e.g., sulfamethoxazole), and certain cephalosporins (e.g. cefoperazone) had the highest anti-persister activity. In addition, some drug candidates, such as daptomycin and clofazimine (which had the highest activity against non-growing persisters), had relatively poor activity or a high minimal inhibitory concentration (MIC) against growing B. burgdorferi. Our findings may have implications for the development of a more effective treatment for Lyme disease and for the relief of long-term symptoms that afflict some Lyme disease patients’
An Optimized SYBR Green I/PI Assay for Rapid Viability Assessment and Antibiotic Susceptibility Testing for Borrelia burgdorferi Jie Feng,Ting Wang,Shuo Zhang,Wanliang Shi,Ying Zhang Published: November 3, 2014
From abstract- ‘The SYBR Green I/PI assay was found to reliably assess the viability of planktonic as well as biofilm B. burgdorferi and could be used as a rapid antibiotic susceptibility test. Thus, the SYBR Green I/PI assay provides a more sensitive, rapid and convenient method for evaluating viability and antibiotic susceptibility of B. burgdorferi and can be used for high-throughput drug screens.’
Drug Combinations against Borrelia burgdorferi Persisters In Vitro: Eradication Achieved by Using Daptomycin, Cefoperazone and Doxycycline Jie Feng,Paul G. Auwaerter,Ying Zhang Published: March 25, 2015
abstract -Although most Lyme disease patients can be cured with antibiotics doxycycline or amoxicillin using 2-4 week treatment durations, some patients suffer from persistent arthritis or post-treatment Lyme disease syndrome. Why these phenomena occur is unclear, but possibilities include host responses, antigenic debris, or B. burgdorferi organisms remaining despite antibiotic therapy. In vitro, B. burgdorferi developed increasing antibiotic tolerance as morphology changed from typical spirochetal form in log phase growth to variant round body and microcolony forms in stationary phase. B. burgdorferi appeared to have higher persister frequencies than E. coli as a control as measured by SYBR Green I/propidium iodide (PI) viability stain and microscope counting. To more effectively eradicate the different persister forms tolerant to doxycycline or amoxicillin, drug combinations were studied using previously identified drugs from an FDA-approved drug library with high activity against such persisters. Using a SYBR Green/PI viability assay, daptomycin-containing drug combinations were the most effective. Of studied drugs, daptomycin was the common element in the most active regimens when combined with doxycycline plus either beta-lactams (cefoperazone or carbenicillin) or an energy inhibitor (clofazimine). Daptomycin plus doxycycline and cefoperazone eradicated the most resistant microcolony form of B. burgdorferi persisters and did not yield viable spirochetes upon subculturing, suggesting durable killing that was not achieved by any other two or three drug combinations. These findings may have implications for improved treatment of Lyme disease, if persistent organisms or detritus are responsible for symptoms that do not resolve with conventional therapy. Further studies are needed to validate whether such combination antimicrobial approaches are useful in animal models and human infection.
Identification of new compounds with high activity against stationary phase Borrelia burgdorferi from the NCI compound collection Jie Feng, Wanliang Shi, Shuo Zhang and Ying Zhang Received 20 March 2015; Revised 22 April 2015; Accepted 8 May 2015
Abstract – Lyme disease is the leading tick-borne disease in the USA. Whereas the majority of Lyme disease patients with early disease can be cured with standard treatment, some patients suffer from chronic fatigue and joint and muscular pain despite treatment, a syndrome called posttreatment Lyme disease syndrome. Although the cause is unclear, ineffective killing ofBorrelia burgdorferi persisters by current Lyme disease antibiotics is one possible explanation. We took advantage of our recently developed high-throughput viability assay and screened the National Cancer Institute compound library collection consisting of 2526 compounds against stationary phase B. burgdorferi. We identified the top 30 new active hits, including the top six anthracycline antibiotics daunomycin 3-oxime, dimethyldaunomycin, daunomycin, NSC299187, NSC363998 and nogalamycin, along with other compounds, including prodigiosin, mitomycin, nanaomycin and dactinomycin, as having excellent activity against B. burgdorferi stationary phase culture. The anthracycline or anthraquinone compounds, which are known to have both anti-cancer and antibacterial activities, also had high activity against growing B. burgdorferi with low minimum inhibitory concentration. Future studies on the structure–activity relationship and mechanisms of action of anthracyclines/anthraquinones are warranted. In addition, drug combination studies with the anthracycline class of compounds and the current Lyme antibiotics to eradicate B. burgdorferi persisters in vitro and in animal models are needed to determine if they improve the treatment of Lyme disease.
Persister mechanisms in Borrelia burgdorferi: implications for improved intervention Jie Feng, Wanliang Shi, Shuo Zhang and Ying Zhang Accepted 5 August 2015
extract ‘Consistent with the persisting organisms not killed by current antibiotics, experiments in various animal models such as mice, dogs and monkeys have shownB. burgdorferi could still be detected after treatment with different Lyme antibiotics though viable organisms could not be cultured. In vitro studies also demonstrated that B. burgdorferi could develop antibiotic tolerant persisters. Although persister mechanisms have been reported in the model organism E. coli, the mechanisms of B. burgdorferi persisters remain unknown.’
The full video of Prof Zhang presentation is now available with others for free at this link http://norvect.no/the-norvect-movies-2015/
