Advancing small-molecule drug leads to inhibit a crucial enzyme in ‘Enterobacterales’ bacteria
Project title: Advancing a direct-acting, small molecule antibacterial with Gram negative specificity and a novel mechanism of action
Some of the most severe bacterial infections, especially in hospital settings, are caused by multi-drug resistance in the Gramnegative group of bacteria known as ‘Enterobacterales’, which includes E. coli and Klebsiella pneumoniae. ArrePath is tackling this challenge by using machine-learning approaches to find and optimise molecules with novel mechanisms of action against multidrug-resistant pathogens. Using this platform, ArrePath identified a series of compounds that inhibit an essential enzyme that is highly conserved across Gram-negative bacteria and has never before been clinically exploited.
Currently, the lead program shows single-digit MIC values against multiple Enterobacterales strains, no in vitro cytotoxicity, and a favorable trajectory toward delivering an oral small molecule therapeutic. With funding and support from PACE, ArrePath aims to advance their project to the lead optimisation stage. They plan to do this by optimising the ADMET/pharmacokinetic properties of their inhibitors, demonstrating in vivo proof of concept for this novel target, and by broadening their spectrum by improving in vitro activity against additional members of the ‘Enterobacterales’ group.
Success for the project will mean delivery of an antibiotic that can treat some of the most serious multi-drug-resistant infections – specifically, complicated urinary tract infections, ventilator-associated bacterial pneumonia and bloodstream infections. In addition, if such an antibiotic is effective when administered orally as well as intravenously, that would help hospitalised patients switch to an easily-taken oral medicine when appropriate.
Company bio:
ArrePath was founded upon the mission to discover new and differentiated classes of anti-infectives to address antimicrobial resistance (AMR) through the application of state-of-the-art technologies and novel strategies.
They apply world-class science and innovation in imaging and AI / ML technologies to identify and develop novel drugs to address global health issues. Their advanced machine learning (ML) drug discovery platform enables a rapid and efficient identification of new drug classes with desired activity profiles and clinical utility, coupled with a deep understanding of mechanism of action at the outset of the discovery process.
PACE is supporting Arrepath with a project in ‘Advancing a direct-acting, small molecule antibacterial with Gram negative specificity and a novel mechanism of action’, advancing small-molecule drug leads to inhibit a crucial enzyme in ‘Enterobacterales’ bacteria.