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.
Although widely considered opportunistic pathogens, nontuberculous mycobacteria (NTM) can cause a wide range of infections in humans. NTM of the M. abscessus complex (MABSC) and Mycobacterium avium complex (MAC) in particular have emerged as important human pathogens globally, causing an increasing number of pulmonary infections among patients with structural lung disease such as COPD, bronchiectasis, and cystic fibrosis (CF). Together MABSC and MAC account for ~95% of the total cases of pulmonary NTM disease reported. Treatment options for NTM pulmonary infections are few and involve lengthy combination regimens of 12-24 months with combinations of intravenous and oral antibiotics that lack bactiero-cidal 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.
DosRST (the two-component regulatory system of Mycobacterium tuberculosis (Mtb)) in 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 and our studies have indicated that the expression of dosRS in MABSC increases ~ 60-fold upon exposure to microaerophilic growth conditions. It has been suggested that inhibition of the DosRS system may prevent NTM infections from being able to form biofilms or remain in a non-replicating state in a host (latent infection), and may be an effective treatment of NTM infection.
- Targets non-replicating, persistent, bacilli
- Expected to potentiate the activity of antibiotics used in combination
- Decrease bacterial burden and reduce pathology
- Dispersed NTM bacilli are more susceptible to killing by the host immune system
- New therapeutics or adjunct therapeutics to treat infections (whether pulmonary or extra pulmonary) caused by nontuberculous mycobacteria.