Inhibitors of Nontuberculous Mycobacteria Biofilms

New Therapeutics to Treat Related Infections

At a Glance

Researchers at Colorado State University have developed a novel therapeutic method for the treatment of nontuberculous mycobacterial (NTM) infections utilizing inhibitors that target the DosRS two-component system of mycobacteria. The treatment then inhibits biofilm formation and bacterial non-replicating persistence under microaerophilic conditions.  Preliminary studies using SCID mouse models of MABSC infection indicated that treatment using these inhibitors led to a significant decrease in bacterial burden within mouse organs when used alone, in the absence of added antibiotics. Further studies have shown when using the DosRS inhibitors as adjunct therapeutics, the inhibitors were further found to potentiate the activity of antibiotics.

Background

Although widely considered opportunistic pathogens, nontuberculous mycobacteria (NTM) can cause a wide range of infections in humans. NTM has emerged as important human pathogens globally, causing an increasing number of lung infections among patients with structural lung disease such as chronic obstructive pulmonary disease (COPD), bronchiectasis, and cystic fibrosis (CF). Treatment options for NTM lung infections are few and involve lengthy regimens of 12-24 months with combinations of intravenous and oral antibiotics that lack bactericidal activity and are associated with significant toxicity. Among the factors thought to contribute to the drug resistance/tolerance of these microorganisms is their ability to persist in a non-replicating state within the host and to form biofilms. Altogether, these concerns place a high priority on the development of innovative approaches to better control and treat NTM infections.

Overview

DosRST (the two-component regulatory system of Mycobacterium tuberculosis (Mtb)) regulates persistence in response to environmental and host immune cues, such as hypoxia, acidic pH, and nutrient starvation. Like Mtb, many NTM are endowed with DosRS systems. Targeting this specific pathway using these inhibitors results in decreased bacterial survival after oxygen depletion, reduced tolerance to a number of antibiotics in vitro and in vivo, and the inhibition of biofilm formation. The inhibitors displayed bactericidal activity comparable to standard-of-care antibiotics in chronically infected mice, in addition to increasing the activity of antibiotics used in combination. Some results can be seen in Figures 1 and 2, and is explained in more detail in the publication linked below.

Benefits

  • Targets non-replicating, persistent, bacteria.
  • Expected to increase the activity of antibiotics used in combination.
  • Decrease bacterial burden and reduce pathology.
  • Dispersed NTM bacilli are more susceptible to the host immune system.

Applications

  • New therapeutics or adjunct therapeutics to treat infections (whether pulmonary or extra pulmonary) caused by nontuberculous mycobacteria.
Last Updated: February 2022
Mycobacterium Tuberculosis Bacteria
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Available for Licensing
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Inventors

Mary Jackson
Juan Belardinelli

Reference Number
2021-033
Licensing Manager

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