Mycobacteriophage–antibiotic therapy promotes enhanced clearance of drug-resistant Mycobacterium abscessus

Abstract

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.

Bacteriophage Therapy for Staphylococcus Aureus Infections: A Review of Animal Models, Treatments, and Clinical Trials

“…In addition to a mature innate immune system, zebrafish embryos are genetically similar to human, and their transparency make them ideal for investigating characteristics of infection mechanisms unreachable in standard animal models. Very recently, several zebrafish studies have been published for evaluating phage treatment upon bacterial infections, though none have studied S. aureus (Easwaran et al, 2017;Johansen et al, 2021;Sundaramoorthy et al, 2021). Bacteria can be injected into the embryo's bloodstream alongside phages, and this treatment was effective with a better survival of the infected zebrafish embryos.…”

A Review on Mycobacteriophages: From Classification to Applications

“…In 2021, the result of a clinical trial on a patient with cystic fibrosis (CF) suffering from a prolonged disseminated infection with M. abscessus , Pseudomonas aeruginosa, EBV viremia (8 years), with a history of two lung transplantations along with administration of various oral/intravenous antibiotics, lumacaftor/ivacaftor, and immunosuppressive drugs (e.g., Clofazimine, bedaquiline, Mycophenolate mofetil, iv rituximab) revealed that the hypodermic administration of mycobacteriophages cocktail containing Muddy (wild type) and engineered BPs33ΔHTH-HRM10 and ZoeJΔ45 every 12 h for seven months (10 9 pfu/dose of each phage) could improve the recovery in this patient [ 16 , 17 , 196 ]. Furthermore, regarding the engineered phages used in the recent study, repressors that induce the lysogenic life cycle in these phages were deleted, and these phages were converted to lytic phages.…”

“…Evidence reveals that most M. abscessus -associated infections are multidrug resistant [ 16 ]. M. abscessus strain GD01 is one of the most-used strains successfully infected with and eliminated by mycobacteriophages such as Muddy, BPs, and ZoeJ [ 196 ].…”

“…Today, mycobacteriophages in isolation/cocktail [ 15 ] or within a synergistic therapy along with antibiotics opened new horizons in the treatment of infections caused by pathogenic mycobacteria [ 16 , 17 , 18 ]. Furthermore, mycobacteriophages have been exploited in diagnostic approaches of slow-/fast-growing mycobacteria through shuttle plasmids that express resistance against antibiotics and induce the production of lysogenic plaques in target mycobacteria [ 19 ]; transduction of nanoluciferase reporter gene cassettes that discriminate viable drug-resistant and -sensitive strains [ 20 ]; phage amplification for detection of antimicrobial resistance species [ 21 , 22 , 23 ]; and viability assessment of target mycobacteria in various samples (i.e., dairy products, blood, stool [ 24 , 25 ]).…”

ALA_PDT Promotes Ferroptosis-Like Death of Mycobacterium abscessus and Antibiotic Sterilization via Oxidative Stress

“…New measures against multi-drug resistant M. abscesses are intensively pursued, such as phage therapy [5,6], natural or synthetic antimicrobial peptide [7] and photodynamic therapy (PDT) [8]. PDT is an emerging treatment modality for diseases with the combination of photosensitive drugs and corresponding wavelengths of light.…”