Mycobacteriophage-antibiotic therapy promotes enhanced clearance of drug-resistant Mycobacterium abscessus.
Matt D JohansenMatthéo AlcarazRebekah M DedrickFrançoise Roquet-BaneresClaire HamelaGraham F HatfullLaurent KremerPublished in: Disease models & mechanisms (2021)
Infection by multidrug-resistant Mycobacterium abscessus is increasingly prevalent in cystic fibrosis (CF) patients, leaving clinicians with few therapeutic options. A compassionate study showed the clinical improvement of a CF patient with a disseminated M. 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 an M. 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 M. abscessus isolates, allowing the identification of drug combinations accompanying phage therapy and treatment prediction in patients. This article has an associated First Person interview with the first author of the paper.
Keyphrases
- cystic fibrosis
- pseudomonas aeruginosa
- drug resistant
- multidrug resistant
- end stage renal disease
- acinetobacter baumannii
- newly diagnosed
- ejection fraction
- chronic kidney disease
- prognostic factors
- lung function
- mycobacterium tuberculosis
- peritoneal dialysis
- escherichia coli
- stem cells
- patient reported outcomes
- chronic obstructive pulmonary disease
- zika virus
- risk assessment
- gram negative
- aedes aegypti
- air pollution
- patient reported