Mycobacterium abscessus (Mab) is a bacterium that poses a particular threat to people with cystic fibrosis (CF) due to its resistance to antibiotics, which enables it to survive even prolonged and aggressive courses of treatment – often involving extended therapy, severe side effects and repeated hospitalisations. 

There are currently no effective treatments for infections caused by this bacterium.

This project aims to develop an approach to combat infections caused by Mab based on a technology called antibody-antibiotic conjugate (AAC). AACs consist of an antibody, which precisely recognises the bacterium, and an antibiotic capable of eliminating it. The antibody binds selectively to Mab and guides the AAC to the bacterium, allowing the complex to be transported into the cells like a ‘Trojan horse’. Once inside, the AAC is broken down, releasing the antibiotic, which can then act directly on the bacterium.

This approach is particularly promising because Mab is able to survive inside macrophages, cells of the immune system that can serve as an important refuge for the bacterium. AACs could therefore enable the bacterium to be targeted even when it is hidden inside cells, concentrating the drug where it is needed and increasing the effectiveness of the treatment, reducing side effects, shortening the duration of treatment and limiting the development of new resistance.

A key aspect of the project is identifying the best targets on the surface of Mab, as no specific antibodies against this bacterium are currently available. To validate the technology, the researchers will use modified bacterial models that display a ‘tag’ on their surface recognised by commercially available antibodies. Subsequently, specific antibodies directed against the bacterium’s natural targets will be developed. The antibiotics to be tested will be azithromycin, apramycin and bedaquiline, which are already used in CF.

The most promising AAC candidates will be tested in cellular models, in ex vivo systems derived from people with CF, and in vivo in animal models in collaboration with the FFC Ricerca CFaCore Service.

The aim is to develop therapeutic candidates, with a view to future inhaled administration. This approach would also offer a high degree of adaptability: indeed, by modifying the antibody, the same technique could be used against other bacteria that cause frequent infections in people with CF.