Phage resistance in Mycobacterium tuberculosis

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Tuberculosis remains a global health threat killing over 1.6 million people annually. Antibiotic treatment for drug-sensitive infections requires three antibiotics for a minimum of six months, and resistance to these antibiotics is common. Newly developed drugs are helpful for treating these resistant infections, but their longevity is challenged by the expectation of further resistances emerging. Tuberculosis is a potential target for therapeutic treatment with bacteriophages, which could be used to treat MDR-TB, XDR-TB, and TDR-TB infections, to shorten standard antibiotic therapy, to reduce the emergence of new resistant strains, to protect and extend the utility of newly developed antibiotics, and potentially to interfere with Mycobacterium tuberculosis transmission. Although phage therapy of TB may face substantial challenges – especially regarding access to the bacterial targets – encouragement is provided by a successful case study in treating a young Cystic Fibrosis patient with a highly antibiotic Mycobacterium abscessus infection. Moreover, the limited genetic variability of M. tuberculosis relative to other bacterial pathogens and preliminary data defining a set of potentially useful mycobacteriophages for treatment, sets the stage for clinical trials to determine if this is an effective and safe strategy for TB control. However, an important puzzle-piece is missing. Currently we know little about the mechanisms of M. tuberculosis resistance to the phages, the orthogonality of shared resistance profiles, or the impact of resistance mutations on virulence or antibiotic susceptibility. Without this, compiling therapeutic phage cocktails relies on guessing which phages are compatible based on genomic diversity, which may correlate only poorly with resistance and co-resistance profiles. Moreover, understanding the genetic basis of resistance provides much needed information required to monitor resistance development during phage therapy trials. Finally, the finding that resistance may commonly inhibit post-DNA injection events suggests that many resistance mechanisms can be thwarted by use of recombinant phages carrying counter-defense genes.