A specific bacteriophage known as Muddy has shown positive results against an antibiotic-resistant strain of Mycobacterium abscessus bacteria. Mycobacterium abscessus bacterial infections are related to cause tuberculosis, leprosy, and severe damage in cystic fibrosis patients. The successful treatment included a combination of phage therapy and antibiotics in a zebrafish model of cystic fibrosis. Researchers from the Université de Montpellier in France, together with researchers from the University of Pittsburgh have published the study Mycobacteriophage–antibiotic therapy promotes enhanced clearance of drug-resistant Mycobacterium abscessus.
Phage Muddy against Mycobacterium abscessus infection
The researchers at Pittsburgh had previously identified a bacteriophage out of 10,000 which was named “Muddy”, that showed promise in killing Mycobacterium abscessus in a petri dish. This made Muddy a perfect candidate for treatment. The zebrafish model was an alternative testing approach towards testing the new therapy in patients. Laurent Kremer, Ph.D., and colleagues at the Université de Montpellier decided to test the combination treatment on zebrafish that carried the key genetic mutation that causes cystic fibrosis in humans and mimics how the immune system responds to bacterial infections. Samples of the resistant form of Mycobacterium abscessus were obtained from a cystic fibrosis patient in order to infect the zebrafish and test the treatment.
Firstly, the fish were monitored for 12 days to observe how the zebrafish reacted to the Mycobacterium abscessus infection. They found that the fish had developed serious infections with abscesses and suffered a high death rate, resulting in only a 20% survival rate.
The team then injected the fish with Muddy and observed changes over 5 days. The fish showed much less severe infections and the survival rate increased to 40%, with fewer abscesses seen in fish during severe infection.
The researchers then treated the zebrafish for 5 days by combining Muddy together with the antibiotic rifabutin. This treatment resulted in the fishes’ infections being less severe and the survival rate to rise to 70% with even fewer abscesses. Researchers said, “this is a dramatic improvement compared to fish treated with only the antibiotic, which had a 40% survival rate”.
Mycobacterium abscessus in cystic fibrosis patients
Mycobacterium abscessus is a bacterium that causes severe damage to the lungs. An infection caused by the multidrug-resistant Mycobacterium abscessus is increasingly prevalent in cystic fibrosis patients and leaves very few therapeutic options. The researchers said that “a compassionate study showed the clinical improvement of a cystic fibrosis patient with a disseminated Mycobacterium abscessus (GD01) infection, following injection of a phage cocktail, including phage Muddy. Broadening the use of phage therapy in patients as a potential antibacterial alternative necessitates the development of biological models to improve the reliability and successful prediction of phage therapy in the clinic”.
“Herein, we demonstrate that Muddy very efficiently lyses GD01 in vitro, an effect substantially increased with standard drugs. Remarkably, this cooperative activity was retained in a Mycobacterium abscessus model of infection in CFTR-depleted zebrafish, associated with a striking increase in larval survival and reduction in pathological signs. The activity of Muddy was lost in macrophage-ablated larvae, suggesting that successful phage therapy relies on functional innate immunity. CFTR-depleted zebrafish represent a practical model to rapidly assess phage treatment efficacy against Mycobacterium abscessus isolates, allowing the identification of drug combinations accompanying phage therapy and treatment prediction in patients”.
The research has demonstrated that it is possible to address and treat antibiotic-resistant bacterial infections caused by Mycobacterium abscessus in zebrafish with the use of specifically targeted bacteriophages. The researchers hope this treatment can be transferred into clinical use to begin saving human lives.
The full study can be viewed in Disease Models & Mechanisms.