Researchers at Virginia Commonwealth University (VCU) say they have identified a key enzyme as a potential therapeutic target for Lyme disease. The enzyme, lactate dehydrogenase (BbLDH), plays a key role in allowing the survival and infectivity of Borrelia burgdorferi, the bacteria responsible for Lyme disease.
“We discovered that BbLDH has a unique biochemical and structural feature and it is essential for B. burgdorferi growth and infectivity,” said study author Chunhao (Chris) Li, MD, of VCU’s School of Dentistry. “BbLDH can serve as an ideal target for developing genus-specific inhibitors that can be potentially used to treat and prevent Lyme disease.”
Details of this research are published in mBio, the journal of the American Society of Microbiology.
Lyme disease is the most commonly reported tick-borne illness in the United States and Europe, affecting hundreds of thousands each year. The bacterium B. burgdorferi has evolved a number of unique mechanisms to thrive in diverse environments, including in the body of a tick and a mammalian host. One key feature is the bacterium’s reliance on BbLDH to maintain its internal redox balance, which is crucial for its survival.
The discovery of BbLDH as a therapeutic target was based on previous work by the VCU researchers, which showed that B. burgdorferi does not use thiamine, a cofactor used by many other organisms, but instead relies on lactate dehydrogenase to convert pyruvate to lactate and maintain a proper NADH/NAD+ ratio. This unique metabolic pathway is crucial for the pathogen’s survival. According to the study’s findings, BbLDH plays a central role in maintaining this energy production and protecting the bacterium from oxidative stress.
To better understand the biochemical and structural features of BbLDH, the investigators used a multidisciplinary approach combining genetics, biochemistry, and crystallography and then performed loss-of-function studies to discover that BbDLH is essential for B. burgdorferi in vitro growth and infectivity in vivo.
To explore the potential for developing new treatments targeting BbLDH, the researchers also conducted high-throughput screening of chemical compounds and identified four potential inhibitors of the enzyme. Two of the identified inhibitors—methoxsalen and medicarpin—showed promise in reducing B. burgdorferi growth, offering a potential pathway for drug development. Both compounds have been used extensively in animal models for studies unrelated to their effects on LDH. Methoxsalen has been researched in combination with ultraviolet light therapy to treat vitiligo. Medicarpin is from a family of isoflavinoids with diverse biological functions that include anti-inflammatory and antimicrobial properties.
The next steps in this research will focus on optimizing the identified inhibitors and exploring their potential for clinical application. The researchers also plan to investigate the potential for these inhibitors to work in combination with other therapies to combat Lyme disease more effectively and potentially to be used as treatments against other tick-borne illnesses.
