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 mycobacteria. The treatment also inhibits continued biofilm formation. Preliminary studies using SCID mouse models 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. When these inhibitors are used as adjunct therapeutics, the activity of antibiotics is increased.
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.
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.
Figure 1. Effect of DosS inhibitors on MABSC survival and drug tolerance under hypoxia.
Figure 2. Effect of DosS inhibitors on MABSC biofilm formation.
- 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.
- New therapeutics or adjunct therapeutics to treat infections (whether pulmonary or extra pulmonary) caused by nontuberculous mycobacteria.