|LYNCH, ADAM - University Of Massachusetts|
|PERSON, PATRICK - University Of Massachusetts|
|SAVINOV, SERGEY - University Of Massachusetts|
|RICH, STEPHEN - University Of Massachusetts|
Submitted to: Journal of Pathogens
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/19/2023
Publication Date: 7/22/2023
Citation: Lynch, A., Person, P., Savinov, S.N., Li, A.Y., Rich, S.M. 2023. Lactate dehydrogenase inhibitors suppress Borrelia burgdorferi growth in vitro. Journal of Pathogens. 12(7):962. https://doi.org/10.3390/pathogens12070962.
Interpretive Summary: Lyme disease is the most common zoonotic illness reported in North America. Borrelia burgdorferi is the causative agent of Lyme disease transmitted by the blacklegged tick, Ixodes scapularis.Current treatment strategies using antibiotics are effective in most cases, but as many as 17% of patients may remain partially symptomatic one year after treatment. Research and development of new chemical compounds that can inhibit the pathogen would not only help improve medical treatment of Lyme disease in humans but also could lead to new products as management tools to interrupt pathogen transmission from the tick vector to humans. USDA ARS scientists teamed up with university researchers to investigate several inhibitors of lactate dehydrogenase (LDH), an enzyme that play a critical role in Borrelia burgdorferi’s ATP production. Laboratory live cell culture experiment results demonstrated that gossypol can fully inhibit spirochetal growth at relatively low concentrations. The study indicates LDH inhibition can be a promising mechanism to suppress Borrelia growth, particularly with bulky LDH inhibitors like gossypol. Further in vivo animal trails would validate the role of gossypol in inhibition of Borrelia growth which may lead to development of a pathogen management tool as part of integrated management of this tick-borne disease. The results obtained from this study are of interest to pharmaceutical companies, pest/vector control companies, vector-borne disease epidemiologists, and researchers who work in the field of vector control and integrated pest management.
Technical Abstract: Borrelia burgdorferi, the causative agent of Lyme disease, has a highly reduced genome and relies heavily on glycolysis for carbon metabolism. As such, established inhibitors of Lactate Dehydrogenase (LDH) were evaluated in culture to determine the extent of their impacts on B. burgdorferi growth. Both racemic and enantiopure (AT-101) gossypol, oxamate, galloflavin, and stiripentol caused dose-dependent suppression of B. burgdorferi growth in vitro. Racemic gossypol and AT-101 were shown to fully inhibit spirochetal growth at concentrations of 70.5 and 187.5 µM, respectively. Differences between racemic gossypol and AT-101 efficacy may be indicative that the dextrorotatory enantiomer of gossypol is a more effective inhibitor of B. burgdorferi growth than the levorotatory enantiomer. As a whole, LDH inhibition appears to be a promising mechanism to suppress Borrelia growth, particularly with bulky LDH inhibitors like gossypol.