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Abstract
Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10–20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi persisters in vitro, even when pre-treated with amoxicillin. These findings may have implications for improved treatment of Lyme disease.
Highlights
Lyme disease may affect multiple organs in disseminated infection and is the most common vector-borne infection reported in the United States and Europe
To qualitatively determine the effect of antibiotics in a highthroughput manner, 10 μl of each compound from the pre-diluted plate or pre-diluted stock was added to 3 days amoxicillin induced round body form from a 5 day-old stationary phase B. burgdorferi culture in the 96-well plate
To identify the best drug combinations with the active hits from the above screens against the round bodies of B. burgdorferi, we evaluated drugs with improved activity detected in this screening including artemisinin, cefmetazole, and sulfachlorpyridazine in combination with drugs identified in the earlier study that appeared to work well against persisters when used in combination (Feng et al, 2015)
Summary
In vitro studies have shown that the round body form of B. burgdorferi is viable and could revert to spirochetal form under suitable conditions (Brorson and Brorson, 1997; Murgia and Cinco, 2004) These round bodies appear to have both lower metabolism and greater resistance to antibiotic treatment, which appears common to stationary phase bacteria in culture generally. Amoxicillin and doxycycline are among the most commonly used frontline drugs for the treatment of Lyme disease, but have poor activity against in vitro, stationary phase cultures enriched with persister forms including round bodies and microcolonies (Kersten et al, 1995; Brorson et al, 2009; Barthold et al, 2010; Sapi et al, 2011; Feng et al, 2015). We sought to investigate whether some non-traditional drugs or drug combinations had improved activity against the amoxicillin-induced round body form as distinct from the previous drug candidates identified from non-antibiotic treated stationary phase culture (Feng et al, 2014a)
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