Urinary tract infection (UTI) by uropathogenic Escherichia coli (UPEC) is one of the most common infections, particularly affecting women. The interaction of FimH, a lectin located at the tip of bacterial pili, with high mannose structures is critical for the ability of UPEC to colonize and invade the bladder epithelium. We describe the synthesis and the in vitro/in vivo evaluation of α-D-mannosides with the ability to block the bacteria/host cell interaction. According to the pharmacokinetic properties, a prodrug approach for their evaluation in the UTI mouse model was explored. As a result, an orally available, low molecular weight FimH antagonist was identified with the potential to reduce the colony forming units (CFU) in the urine by 2 orders of magnitude and in the bladder by 4 orders of magnitude. With FimH antagonist, the great potential for the effective treatment of urinary tract infections with a new class of orally available antiinfectives could be demonstrated.
The initial step for the successful establishment of urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli, is the adhesion of bacteria to urothelial cells. This attachment is mediated by FimH, a mannose-binding adhesin, which is expressed on the bacterial surface. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed, avoiding selection pressure and thereby implying a reduced risk of resistance. Here, we present a new class of highly active antimicrobials, targeting the virulence factor FimH. When the most potent representative, an indolinylphenyl mannoside, was administered in a mouse model at the low dosage of 1 mg/kg (corresponding to approximately 25 μg/mouse), the minimal therapeutic concentration to prevent UTI was maintained for more than 8 h. In a treatment study, the colony-forming units in the bladder could be reduced by almost 4 orders of magnitude, comparable to the standard antibiotic treatment with ciprofloxacin (8 mg/kg, sc).
Urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), belong to the most prevalent infectious diseases worldwide. The attachment of UPEC to host cells is mediated by FimH, a mannose-binding adhesin at the tip of bacterial type 1 pili. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed. Here, we describe the development of an orally available FimH antagonist. Starting from the carboxylate substituted biphenyl α-d-mannoside 9, affinity and the relevant pharmacokinetic parameters (solubility, permeability, renal excretion) were substantially improved by a bioisosteric approach. With 3'-chloro-4'-(α-d-mannopyranosyloxy)biphenyl-4-carbonitrile (10j) a FimH antagonist with an optimal in vitro PK/PD profile was identified. Orally applied, 10j was effective in a mouse model of UTI by reducing the bacterial load in the bladder by about 1000-fold.
A large unmet medical need exists for safer antithrombotic drugs because all currently approved anticoagulant agents interfere with hemostasis, leading to an increased risk of bleeding. Genetic and pharmacologic evidence in humans and animals suggests that reducing factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with a minimal risk of bleeding. We generated a fully human antibody (MAA868) that binds the catalytic domain of both FXI (zymogen) and activated FXI. Our structural studies show that MAA868 traps FXI and activated FXI in an inactive, zymogen-like conformation, explaining its equally high binding affinity for both forms of the enzyme. This binding mode allows the enzyme to be neutralized before entering the coagulation process, revealing a particularly attractive anticoagulant profile of the antibody. MAA868 exhibited favorable anticoagulant activity in mice with a dose-dependent protection from carotid occlusion in a ferric chloride–induced thrombosis model. MAA868 also caused robust and sustained anticoagulant activity in cynomolgus monkeys as assessed by activated partial thromboplastin time without any evidence of bleeding. Based on these preclinical findings, we conducted a first-in-human study in healthy subjects and showed that single subcutaneous doses of MAA868 were safe and well tolerated. MAA868 resulted in dose- and time-dependent robust and sustained prolongation of activated partial thromboplastin time and FXI suppression for up to 4 weeks or longer, supporting further clinical investigation as a potential once-monthly subcutaneous anticoagulant therapy.
Urinary tract infections (UTIs) are caused primarily by uropathogenic Escherichia coli (UPEC), which encode filamentous surface-adhesive organelles called type 1 pili. FimH is located at the tips of these pili. The initial attachment of UPEC to host cells is mediated by the interaction of the carbohydrate recognition domain (CRD) of FimH with oligomannosides on urothelial cells. Blocking these lectins with carbohydrates or analogues thereof prevents bacterial adhesion to host cells and therefore offers a potential therapeutic approach for prevention and/or treatment of UTIs. Although numerous FimH antagonists have been developed so far, few of them meet the requirement for clinical application due to poor pharmacokinetics. Additionally, the binding mode of an antagonist to the CRD of FimH can switch from an in-docking mode to an out-docking mode, depending on the structure of the antagonist. In this communication, biphenyl α-D-mannosides were modified to improve their binding affinity, to explore their binding mode, and to optimize their pharmacokinetic properties. The inhibitory potential of the FimH antagonists was measured in a cell-free competitive binding assay, a cell-based flow cytometry assay, and by isothermal titration calorimetry. Furthermore, pharmacokinetic properties such as log D, solubility, and membrane permeation were analyzed. As a result, a structure-activity and structure-property relationships were established for a series of biphenyl α-D-mannosides.
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