Antibiotic resistance continues to be a major global health risk with an increase in multi-drug resistant infections seen across nearly all bacterial diseases. Mycobacterial infections such as Tuberculosis (TB) and Non-Tuberculosis infections have seen a significant increase in the incidence of multi-drug resistant and extensively drug-resistant infections. With this increase in drug-resistant Mycobacteria, mycobacteriophage therapy offers a promising alternative. However, a comprehensive study on the infection dynamics of mycobacteriophage against their host bacteria and the evolution of bacteriophage (phage) resistance in the bacteria remains elusive. We aim to study the infection dynamics of a phage cocktail against Mycobacteria under various pathophysiological conditions such as low pH, low growth rate and hypoxia. We show that mycobacteriophages are effective against M. smegmatis under various conditions and the phage cocktail prevents emergence of resistance for long durations. Although the phages are able to amplify after infection, the initial multiplicity of infection plays an important role in reducing the bacterial growth and prolonging efficacy. Mycobacteriophages are effective against antibiotic-resistant strains of Mycobacterium and show synergy with antibiotics such as rifampicin and isoniazid. Finally, we also show that mycobacteriophages are efficient against M. tuberculosis both under lag and log phase for several weeks. These findings have important implications for developing phage therapy for Mycobacterium.

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Antibiotic resistance continues to be a major global health risk with an increase in multi-drug resistant infections seen across nearly all bacterial diseases. This global burden is further pronounced by the misuse of antibiotics and the availability of only a handful of antibiotics in the development pipeline. Amongst the drug-resistant infections, mycobacterial infections such as Tuberculosis (TB) and Non-Tuberculosis infections have seen a significant increase in the incidence of multi-drug resistant and extensively drug-resistant infections. With this increase in drug-resistant Mycobacteria, mycobacteriophage therapy offers a promising alternative. However, a comprehensive study on the infection dynamics of mycobacteriophage against their host bacteria and the evolution of bacteriophage (phage) resistance in the bacteria remains elusive. We aim to study the infection dynamics of a mixture of phage against Mycobacteria under various pathophysiological conditions such as low pH, low growth rate and hypoxia. We show that mycobacteriophages are effective against M. smegmatis under various conditions and that the mixture of phages prevents the 2 evolution of resistance for long durations. Mycobacteriophages are effective against antibiotic-resistant strains of Mycobacterium and show synergy with antibiotics. Finally, we also show that mycobacteriophages are infective and efficient against M. tuberculosis and prevent its growth for several weeks. These findings have important implications for developing phage therapy against Mycobacterium.