Washington, D.C.-Researchers have discovered that an enzyme can serve as an ideal target for developing new therapeutics against Lyme disease and, likely, other tick-borne diseases, as well. The finding was reported in mBio, a journal of the American Society for Microbiology.
Lyme disease is the most commonly reported tick-borne illness in the U.S. and Europe. Its causative pathogen, Borrelia burgdorferi, has evolved unique metabolic pathways to cope with its enzootic life cycle, some of which are specific and ideal targets for developing new ways to treat Lyme disease.
In their previous work, researchers at Virginia Commonwealth University found that B. burgdorferi does not use thiamin as a cofactor and, instead, relies on lactate dehydrogenase (BbLDH) to convert pyruvate to lactate to balance the NADH/NAD+ ratio. This pathway has not been reported in any other microorganisms. The NADH/NAD+ ratio plays a crucial role in regulating the intracellular redox state, which impacts cell survival.
In the new study, the researchers sought to establish the role of BbLDH in the pathophysiology of B. burgdorferi and explore its potential as a new therapeutic target. They first elucidated the biochemical and structural features of BbLDH using an approach of genetics, biochemistry and X-ray crystallography. Next, they performed loss-of-function studies and found that BbLDH is essential for B. burgdorferi in vitro growth and in vivo infectivity. The researchers also conducted high-throughput screening and discovered several new LDH inhibitors.
"We discovered that BbLDH has a unique biochemical and structural feature, and it is essential for B. burgdorferi growth and infectivity," said corresponding study author Chunhao (Chris) Li, M.S., M.D., Edward Myers Endowed Professor, the Philips Research Institute for Oral Health, School of Dentistry, Virginia Commonwealth University. "BbLDH can serve as an ideal target for developing genus-specific inhibitors that can be potentially used to treat and prevent Lyme disease."
The impact of Lyme disease on public health fuels an emerging demand for novel therapeutics to treat Lyme disease. "This report also sheds new light into understanding the role of LDH in the pathophysiology of other tick-borne pathogens," Li said.
