Small Molecule Glycoside Inhibitors of LecB for the Treatment of Pseudomonas Infections

Project Summary/Abstract Pseudomonas aeruginosa (Pa) is a Gram-negative bacterium and opportunistic pathogen capable of persisting in diverse environments and causing numerous human infections including: skin, soft tissue, joint, blood stream, and lung infections. Pa infections most frequently occur in patients with compromised immune or barrier functions, especially in patients with compromised lung function such as those with cystic fibrosis (CF) or chronic obstructive pulmonary disease. Once established, Pa infections are increasingly difficult to treat as the high mutation rate and the promiscuous acquisition of mobile genetic elements containing antimicrobial resistance systems by Pa has augmented its already high intrinsic antibiotic resistance, resulting in the emergence of antimicrobial resistant (AMR) Pa isolates. Pa infections, especially those caused by AMR Pa, result in high levels of morbidity and mortality and dramatically increase healthcare costs to afflicted patients. Therefore, new and safe drugs, with novel mechanisms of action are desperately needed to effectively treat Pa infections and reduce the emergence AMR Pa. Further exacerbating this high AMR is the ability of Pa to form biofilms in environmental and host niches. Biofilms are complex communities of bacteria incased in a polymeric matrix that reduce the efficacy of antimicrobials by numerous mechanisms. The use of biofilm inhibitory compounds has been shown to enhance the efficacy of antibiotics in in vitro systems and in in vivo Pa infection models suggesting that this strategy could help alleviate the AMR Pa burden. The Pa lectin, LecB, is a fucose and mannose binding protein that is essential for biofilm formation and contributes to pathogenesis. The inhibition of LecB function using exogenously administered fucose- and/or mannose-based binding antagonists reduces in vitro biofilm formation and enhances the efficacy of antibiotics in in vivo models of Pa lung infection. Fimbrion is collaborating with Dr. Alexander Titz to develop a small molecule series of high affinity fucose- based glycomimetics that target the LecB sugar binding site. The current series of LecB antagonists display increased potency (up to 200-fold more potent than fucose), excellent in vitro solubility and stability with good in vivo oral bioavailability (34%). Critically, an early lead LecB inhibitor is able to enhance the efficacy of tobramycin in a mouse model of Pa lung infection, providing proof-of-principle for this approach. In Aim 1 of our SBIR Phase I, we will focus on generating a library of LecB inhibitors with optimized potency and pharmacokinetic (PK) properties, while maintaining tge solubility, safety, and stability properties of the early compounds. In Aim 2 we will test a set of compounds with the best combination of the above characteristics for in vivo safety in a maximum tolerated dose study, for dose/exposure linearity in a dose escalation PK study, and for efficacy in a mouse model of Pa lung infection. Success in this Phase I project will be defined as identifying potent and orally bioavailable LecB inhibitors with sufficiently large therapeutic widows to allow the dosing necessary to achieve antibiotic enhancing activity in mouse models of Pa lung infection.