MmpL3 Inhibitor Screening Assays

At a Glance

​Because of the growing interest in MmpL3 as the putative target of multiple new small molecule inhibitors of Mtb and NTM, Researchers at Colorado State University have developed screening assays required to assess the selectivity and mechanism of action of MmpL3 inhibitors.

Background

The continuing rise of multidrug-resistant tuberculosis (TB) throughout the world places a high priority on the development of new anti-TB drugs with bactericidal mechanisms different from those of presently available agents. Non-tuberculous mycobacteria (NTM), on the other hand, are intrinsically resistant to antibiotics and the infections they cause are notoriously difficult to treat. In the last 8 years, the screening of compound libraries against Mycobacterium tuberculosis (Mtb) and NTM species in culture followed by the whole genome sequencing of spontaneous resistant mutants has identified multiple small molecule inhibitors apparently targeting an essential mycolic acid transporter discovered in the Jackson laboratory in 2012, known as MmpL3 (Grzegorzewicz et al., 2012; Nat. Chem. Biol.). One of these inhibitors, SQ109, is undergoing clinical trials and at least two other series of MmpL3 inhibitors (urea- and indolecarboxamide-based chemotypes) are currently under development for their potential to reduce treatment duration and kill MDR Mtb isolates while lacking untoward effects on the human cytochrome P450 enzymes that metabolize antivirals.

Primarily, due to the lack of MmpL3-specific assays this transporter has not yet been validated as the direct target of most of these inhibitors. Data published in 2014 by the Jackson laboratory indicate that some series of compounds may in fact be inhibiting the transporter indirectly through the dissipation of the proton motive force (Li et al., 2014; Antimicrob. Agents Chemother.).

Benefits

  • Assay can be performed on intact Mycobacterium bacilli
  • Can be adapted to any mycobacterial ortholog of the MmpL3 protein
  • Can be adapted to the screening of inhibitors against the purified MmpL3 protein(s)

Applications

  • Drug discovery
Last Updated: November 2019
Test tubes in a lab
Opportunity

Available for Licensing

IP Status
Inventors

Mary Jackson
Wei Li
Mercedes Gonzalez-Juarrero

Reference Number
19-072
Licensing Manager

Jessy McGowan
Jessy.McGowan@colostate.edu
970-491-7100