title: Borreliacidal activity of Borrelia metal transporter A (BmtA) binding small molecules by manganese transport inhibition.
abstract: Borrelia burgdorferi, the causative agent of Lyme disease, utilizes manganese (Mn) for its various metabolic needs. We hypothesized that blocking Mn transporter could be a possible approach to inhibit metabolic activity of this pathogen and eliminate the infection. We used a combination of in silico protein structure prediction together with molecular docking to target the Borrelia metal transporter A (BmtA), a single known Mn transporter in Borrelia and screened libraries of FDA approved compounds that could potentially bind to the predicted BmtA structure with high affinity. Tricyclic antihistamines such as loratadine, desloratadine, and 3-hydroxydesloratadine as well as yohimbine and tadalafil demonstrated a tight binding to the in silico folded BmtA transporter. We, then, tested borreliacidal activity and dose response of the shortlisted compounds from this screen using a series of in vitro assays. Amongst the probed compounds, desloratadine exhibited potent borreliacidal activity in vitro at and above 78 μg/mL (250 μM). Borrelia treated with lethal doses of desloratadine exhibited a significant loss of intracellular Mn specifically and a severe structural damage to the bacterial cell wall. Our results support the possibility of developing a novel, targeted therapy to treat Lyme disease by targeting specific metabolic needs of Borrelia.
authors.affiliation: Biomaterials and Advanced Drug Delivery Laboratory, Stanford Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA, USA.
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Wagh
authors.affiliation: Biomaterials and Advanced Drug Delivery Laboratory, Stanford Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA, USA.
authors.forename: Venkata Raveendra
authors.initials: VR
authors.lastname: Pothineni
authors.affiliation: Biomaterials and Advanced Drug Delivery Laboratory, Stanford Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Inayathullah
authors.affiliation: Biomaterials and Advanced Drug Delivery Laboratory, Stanford Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.affiliation: Biomaterials and Advanced Drug Delivery Laboratory, Stanford Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA, USA.
authors.forename: Kwang-Min
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Biomaterials and Advanced Drug Delivery Laboratory, Stanford Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA, USA.
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Rajadas
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D025065:Borrelia burgdorferi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006633:Histamine Antagonists / Q000494:pharmacology*; D008345:Manganese / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D027682:Cation Transport Proteins; D006633:Histamine Antagonists; D008345:Manganese
keywords: Bac Titer-Glo assay; BmtA; Borrelia burgdorferi; Lyme disease; desloratadine