Effect of Microenvironment on the Activity of Mycobacteriophages for Treating Mycobacterium abscessus

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Novel therapies are needed to control the growing problem of antibiotic-resistant bacterial infections. Bacteriophages (phages) are viruses that infect and kill bacteria. Because phages and antibiotics differ in their killing mechanisms, phage therapy is a potential strategy for prevention and treatment of drug resistant bacteria. Drug resistant nontuberculous mycobacteria (NTM) infections are on the rise and they are a significant threat for people with underlying lung diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) or non-CF bronchiectasis. Mycobacterium abscessus is one of the most common NTMs encountered in pulmonary NTM disease and it is the most difficult to treat. M. abscessus is extremely drug resistant and there is no systematically proven regimen that is effective. Phage therapy, involving a cocktail of three mycobacteriophages (mycophages), was recently employed under compassionate use conditions to treat disseminated M. abscessus disease in a CF patient. This mycophage treatment was associated with clinical improvement of the patient. However, the M. abscessus infection of the patient has yet to fully resolve and twice-daily treatment with intravenous mycophages is ongoing two years later. The limitations of the ongoing mycophage treatment are unknown. A significant gap in knowledge for phage therapy is whether phages can interact with their host bacteria in the different microenvironments encountered during infection. M. abscessus is able to both survive intracellularly in macrophages and extracellularly in biofilms. Whether mycophages can kill M. abscessus in these environments is unknown. The ability of mycophages to traverse and act in normal mucus or pathological CF mucus is also unknown. Working with a collection of M. abscessus isolates and mycophages, including those from the ongoing clinical case, we will evaluate the impact of each of these potential barriers (macrophages, biofilms, and mucus) on mycophage activity. The results of these studies will shed light on microenvironments that may limit phage activity for M. abscessus specifically and, more broadly, inform on potential challenges to phage therapy for intracellular, biofilm forming, and pulmonary bacterial pathogens. We expect the knowledge gained will drive development of strategies to improve phage therapy as an option to prevent and treat drug resistant bacterial infections. Given the need for therapies to treat M. abscessus, this R21 is responsive to NOT-AI-17-016 (Notice of NIAID’s Interest in Biomedical Research in non-AIDS associated, Pulmonary Non- Tuberculous Mycobacterial (NTM) Infections).