Columbia Technology Ventures

Platform for identifying therapeutics targeting Mycobacterium tuberculosis

This technology is a treatment development platform that leverages structural information from genetically engineered pathogen-specific enzyme crystals to inform the design of targeted therapeutics against Mycobacteria.

Unmet Need: Drug screen for compounds that target Mycobacteria

Current methods to treat tuberculosis involve targeted inhibition of enzymes critical to bacterial function. While these regiments are effective, patients can struggle to complete treatment programs due to the negative consequences of off-target effects. Incomplete adherence to antibiotic regiments can drive the growth and evolution of surviving bacteria, resulting in worsening symptoms or the development of treatment-resistant forms of tuberculosis. Second-line treatment regiments are longer, more rigorous, and come with more serious side effects, suggesting a need to improve the efficacy and specificity of drugs used in first-line treatment of tuberculosis.

The Technology: Effective structure-based design of therapeutics targeting Mycobacteria

This technology uses the genetically-engineered crystal structure of a critical Mycobacterium-specific enzyme to inform the development of more targeted and effective tuberculosis treatments. Phosphatidylinositol-phosphate synthase (PIPS) is essential for catalyzing the synthesis of phosphatidylinositol, which makes up the membrane of Mycobacteria, making this a potent potential drug target. This method can be used to screen for compounds that disrupt the Mycobacterium tuberculosis (M. tuberculosis) inositol phosphate binding site as well as identifying inhibitors of PIPS. As a result, by combining genetically engineered bacterial components and crystallography studies to generate structural information for the design of therapeutics against Mycobacteria, this technology represents an improved, specific approach to identify binding sites for Mycobacterial drug targets.

Crystallization constructs generated using this technology have been functionally validated.

Applications:

  • Drug screening
  • Therapeutic target identification against Mycobacteria
  • Method for targeting other key pathogenic proteins

Advantages:

  • Target enzyme-substrate pair is unique to M. tuberculosis, minimizing potential off-target effects
  • Engineered crystal provides high-resolution enzyme structure information
  • Approach can be expanded to investigate other enzymes critical to pathogenic bacteria
  • Structural information can be used to create in vitro models to test and evaluate treatments

Lead Inventor:

Filippo Mancia, Ph.D.

Patent Information:

Patent Pending (WO/2017/053458)

Related Publications:

Tech Ventures Reference: