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
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
Correspondence: Y Zhang, E-mail: yzhang@jhsph.edu
Received 20 March 2015; Revised 22 April 2015; Accepted 8 May 2015
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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.
'Of the 2526 compounds in the NCI compound library collection tested, 237 were found to have higher activity against B. burgdorferi persisters than doxycycline and amoxicillin in the primary screen.'
'In summary, we identified the anthracycline class of compounds including daunomycin, daunomycin 3-oxime, dimethyldaunomycin, NSC299187, NSC363998, and nogalamycin along with some other compounds, including prodigiosin, mitomycin, nanaomycin, and dactinomycin, as having excellent activity against both the non-growing stationary phase and growing B. burgdorferi cultures. The structure–activity relationship and mechanisms of action of the anthracycline/anthraquinone class of compounds against B. burgdorferi persisters should be addressed in future studies. In addition, drug combination studies with the anthracycline class of compounds and the current Lyme antibiotics are required to assess whether they improve treatment of Lyme disease in animal models and in patients.'
This latest study follows on from earlier studies posted about
Earlier posts on work by Prof Zhang
and
Prof Ying Zhang is due to present at this year's LDA conference
Other interesting research on treating Borrelia persister cells by Prof Kim Lewis
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