Subject Category: Antimicrobials and drug resistance
Citation: Emerging Microbes & Infections (2014) 3, e49; doi:10.1038/emi.2014.53
Published online 2 July 2014
Published online 2 July 2014
Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library
OPEN
Jie Feng1, Ting Wang1, Wanliang Shi1, Shuo Zhang1, David Sullivan1, Paul G Auwaerter2 and Ying Zhang1
1Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
- 2Fisher Center for Environmental Infectious Diseases, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
Correspondence: Y Zhang, E-mail: yzhang@jhsph.edu
Received 17 April 2014; Revised 30 May 2014; Accepted 3 June 2014
- 2Fisher Center for Environmental Infectious Diseases, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
Correspondence: Y Zhang, E-mail: yzhang@jhsph.edu
Received 17 April 2014; Revised 30 May 2014; Accepted 3 June 2014
ABSTRACT
Although antibiotic treatment for Lyme disease is effective in the majority of cases, especially during the early phase of the disease, a minority of patients suffer from post-treatment Lyme disease syndrome (PTLDS). It is unclear what mechanisms drive this problem, and although slow or ineffective killing of Borrelia burgdorferi has been suggested as an explanation, there is a lack of evidence that viable organisms are present in PTLDS. Although not a clinical surrogate, insight may be gained by examining stationary-phase in vitro Borrelia burgdorferi persisters that survive treatment with the antibiotics doxycycline and amoxicillin. To identify drug candidates that can eliminate B. burgdorferi persisters more effectively, we screened an Food and Drug Administration (FDA)-approved drug library consisting of 1524 compounds against stationary-phase B. burgdorferi by using a newly developed high throughput SYBR Green I/propidium iodide (PI) assay. 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.
Although antibiotic treatment for Lyme disease is effective in the majority of cases, especially during the early phase of the disease, a minority of patients suffer from post-treatment Lyme disease syndrome (PTLDS). It is unclear what mechanisms drive this problem, and although slow or ineffective killing of Borrelia burgdorferi has been suggested as an explanation, there is a lack of evidence that viable organisms are present in PTLDS. Although not a clinical surrogate, insight may be gained by examining stationary-phase in vitro Borrelia burgdorferi persisters that survive treatment with the antibiotics doxycycline and amoxicillin. To identify drug candidates that can eliminate B. burgdorferi persisters more effectively, we screened an Food and Drug Administration (FDA)-approved drug library consisting of 1524 compounds against stationary-phase B. burgdorferi by using a newly developed high throughput SYBR Green I/propidium iodide (PI) assay. 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.
Keywords:
Borrelia burgdorferi; drug discovery; FDA approved drug library; persisters; SYBR Green I
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Interesting discussion on this important paper on Lymenet Europe forum thanks to Camp Other
'Lyme Research Alliance has been funding Dr. Kim Lewis' team to do research on Borrelia burgdorferi persister cells and to find a treatment that will kill persisters (either a new antibiotic or antibiotic and an additional drug/metabolite which awakens dormant cells).
Today, an open access paper has been published by Nature by both Auwaerter (who has been adamant that people cannot get persistent infections with Lyme disease) and Zhang, who has worked on persister cells and published in Nature prior to this about them. Zhang and Lewis have done persister research together.
In an interesting turn of events, Auwaerter and Zhang and co. have been doing research on FDA-approved drugs already in their database which may work on Borrelia persister cells. While Auwaerter issues his usual caveats that there isn't established evidence of persistent infection in people with post treatment Lyme disease/chronic Lyme disease, it is notable that he would be working on this kind of research and write about the uncertainties concerning Lyme disease.'
http://www.lymeneteurope.org/forum/viewtopic.php?f=5&t=5419
An excellent explanation about the difference between antibiotic resistance and persister cells found on Camp Other blog here
Borrelia burgdorferi; drug discovery; FDA approved drug library; persisters; SYBR Green I
-------------------------------------------------------------------------
Interesting discussion on this important paper on Lymenet Europe forum thanks to Camp Other
'Lyme Research Alliance has been funding Dr. Kim Lewis' team to do research on Borrelia burgdorferi persister cells and to find a treatment that will kill persisters (either a new antibiotic or antibiotic and an additional drug/metabolite which awakens dormant cells).
Today, an open access paper has been published by Nature by both Auwaerter (who has been adamant that people cannot get persistent infections with Lyme disease) and Zhang, who has worked on persister cells and published in Nature prior to this about them. Zhang and Lewis have done persister research together.
In an interesting turn of events, Auwaerter and Zhang and co. have been doing research on FDA-approved drugs already in their database which may work on Borrelia persister cells. While Auwaerter issues his usual caveats that there isn't established evidence of persistent infection in people with post treatment Lyme disease/chronic Lyme disease, it is notable that he would be working on this kind of research and write about the uncertainties concerning Lyme disease.'
An excellent explanation about the difference between antibiotic resistance and persister cells found on Camp Other blog here
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