Mycobacterium abscessus (Mab) causes chronic lung disease and has been associated with poor clinical outcomes in people with cystic fibrosis (CF) after lung transplants.  This is due to Mab’s extensive resistance to antibiotics. 

Drug therapy against Mab is extremely time-consuming (it can take up to 2 years) and relies on antibiotic regimens with major, even severe, side effects such as nausea, deafness and impaired liver function, and its failure results in an accelerated decline in lung function. It is therefore necessary to find a new approach that solves this therapeutic limitation: in this project, the researchers propose a therapy other than classical antibiotics to eradicate Mab, to avoid the emergence of resistance by exploiting the natural mechanisms of bacteriophages to infect and kill bacteria.

The researchers produced, purified and characterised molecules called endolysins, proteins produced by bacteriophages (i.e. viruses that specifically attack bacteria), and validated their ability to bind effectively to the bacterium’s membrane. In particular, endolysins selective against Mab were used.
They also optimised an assay for quantifying biofilm production by Mab within human macrophages, as biofilm is the main culprit in aggravating infections.

Endolysins were subsequently tested for their ability to eliminate both extra- and intracellular Mab: in particular, an endolysin was obtained that was capable of efficiently eliminating extracellular Mab, as demonstrated by the bacterium’s decreased viability, but was still ineffective in eliminating intracellular Mab.

It is therefore necessary to improve the transport of endolysin within infected cells: under current conditions, the protein cannot penetrate the cell membrane and enter the cytoplasm where Mab resides.  For this purpose, nanoparticles will be developed to transport endolysin inside the cells.