Antimycobacterial potential of Mycobacteriophage under disease-mimicking conditions

Abstract

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.

Antimycobacterial Potential of Mycobacteriophage Under Disease-Mimicking Conditions

“…We thank the Molecular Reproduction, Development and Genetics, and Materials Engineering common facility for instrument access. The manuscript has been released as a pre-print at BioRxiv ( Kalapala et al, 2020 ).…”

A natural broad-spectrum inhibitor of enveloped virus entry, effective against SARS-CoV-2 and Influenza A Virus in preclinical animal models

“…The following cell lines were used in this study: HEK293T cells expressing human ACE2 (NR-52511, BEI Resources, NIAID, NIH); HEK293T (NCCS, Pune, amplified in M. smegmatis and phage enumeration was done using the soft agar overlay technique as reported by Kalapala et al (Kalapala et al, 2020).…”

“…C, SRM University, Andhra Pradesh. TM4 mycobacteriophage (Bajpai et al, 2018) was amplified in M. smegmatis and phage enumeration was done using the soft agar overlay technique as reported by Kalapala et al (Kalapala et al, 2020).…”

Combatting intracellular pathogens using bacteriophage delivery

“…A recent study has reported that a cocktail of phages was effective in inhibiting M. smegmatis growth under acidic, hypoxic and stationary phase growth conditions [107].…”

“…This would ensure that the evolving phage-resistant population will still be susceptible to other phages in the cocktail [110][111][112]. A phage cocktail was shown to reduce development of phage tolerance in M. smegmatis and M. tuberculosis compared to treatment with single phages [107]. Broad-range lytic phages need to be identified or developed and tested against clinical strains and demographically predominant strains in addition to lab strains [113][114][115].…”