Whole Cell Active Inhibitors of Mycobacterium Tuberculosis Lipoamide Dehydrogenase

Background & Unmet Need

• Tuberculosis (TB) infected 10 M and killed 1.5 M people in 2018, and remains a worldwide health crisis due to rising drug resistance
• The BPaL regimen (bedaquiline, pretomanid, and linezolid) received FDA approval in 2019 and is the first regimen in decades to feature novel MOAs
• However, there is a need to develop additional inhibitor classes to novel targets, to sustain the TB drug pipeline and shorten and diversify drug regimens
• Lipoamide dehydrogenase (Lpd) is a promising therapeutic target but has yet to be chemically validated
• Mtb lacking Lpd fails to grow on carbohydrates as a sole carbon source and connect establish TB infection in mice
• Unmet Need: Novel classes of Mtb inhibitors targeted unexplored targets such as Lpd

Technology Overview

• The Technology: Improved sulfonamide-based Lpd inhibitors that exhibit acceptable Mtb permeability and phenocopy lpd genetic deletion in vitro
• Through an extensive structure-activity relationship (SAR) campaign, compound 13 emerged as the lead candidate with the lowest minimum inhibitory concentration (MIC) and highest pyruvate fold increase
• Compound 13 was shown to be a potent, time-dependent, slowly dissociating inhibitor of Mtb Lpd
• PoC Data: Compound 13 selectively kills Mtb under nitrosative stress and inhibits the growth of Mtb inside mouse bone marrow-derived macrophages (BMDM)
• NB: Compound 13 not tested for efficacy in TB mouse model due to high susceptibility to mouse microsomal metabolism
• Development of next-generation analogs is ongoing

Technology Applications

• Treatment and prevention of Mtb infection
• Inclusion in combination regimens to combat Mtb resistance

Technology Advantages

• Highly selective for mycobacterial Lpd over the human enzyme, reducing risk of off-target effects
• Compound 13 is a slowly-dissociating inhibitor of Mtb Lpd
• No toxicity to mouse bone marrow-derived macrophages (BMDM) and HEPG2 cells was observed below 100μM