Decoding phage resistance by mpr and its role in survivability of Mycobacterium smegmatis

Bacteria and bacteriophages co-evolve in a constant arms race, wherein one tries and finds newer ways to overcome the other. Phage resistance poses a great threat to the development of phage therapy. Hence, it is both essential and important to understand the mechanism of phage resistance in bacteria. First identified in Mycobacterium smegmatis, the gene mpr, upon overexpression, confers resistance against D29 mycobacteriophage. Presently, the mechanism behind phage resistance by mpr is poorly understood. Here we show that Mpr is a membrane-bound DNA exonuclease, which digests DNA in a non-specific manner independent of the sequence, and shares no sequence or structural similarity with any known nuclease. Exonuclease activity of mpr provides resistance against phage infection, but the role of mpr may very well go beyond just phage resistance. Our experiments show that mpr plays a crucial role in the appearance of mutant colonies (phage resistant strains). However, the molecular mechanism behind the emergence of these mutant/resistant colonies is yet to be understood. Nevertheless, it appears that mpr is involved in the survival and evolution of M. smegmatis against phage. A similar mechanism may be present in other organisms, which requires further exploration.