Analysis of Novel Inhibitors of Borrelia MTA/SAH Nucleosidases
Lyme disease is a tick-transmitted illness caused by the spirochaete Borrelia burgdorferi. If left untreated, Lyme disease can lead to serious health problems such as paralysis, muscle weakness, and crippling “Lyme arthritis”. In 2014, the CDC reported over 25,000 confirmed cases of Lyme disease in the U.S, but it is estimated that the actual number of cases could be ten times higher. Although there are existing antibiotics for Lyme disease (e.g. doxycycline, amoxicillin, cefuroxime axetil, etc), some patients display intolerance to these treatments. Here we report the development of alternative drugs that target three Borrelia Methylthioadenosine/S-adenosylhomocysteine nucleosidases (MTA/SAH MTNs): surface-bound Borrelia Glycosaminoglycan-binding Protein (BGP), secreted MtnN, and cytoplasmic PFS. MTA/SAH nucleosidase activity, is a key component in the adenine and methionine salvage pathways and is an essential part of Borrelia burgdorferi metabolic activity. Novel nucleosidase inhibitors were identified from in silico screening of drug databases. A series of subsequent compounds were synthesized based on the lead compounds, and their inhibitory activity against BGP, MtnN, and PFS assessed using spectrophotometric enzyme assays. Several of the compounds show promising anti-nucleosidase activity and in vitro antibiotic activity against Borrelia cultures. This work provides the basis for further development of these drugs as novel Lyme disease treatments.
Gonzalez, Jesus; Firica, Tudor; Mimenza, Amaia; and Lines, Elias, "Analysis of Novel Inhibitors of Borrelia MTA/SAH Nucleosidases" (2017). 2017 Undergraduate Research and Scholarship Conference.