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Towards restoring antibiotic sensitivity in Mycobacterium tuberculosis using bacteriophages

J C Evans(1) E O Johnson(1)

1:The Francis Crick Institute

The global rise in antimicrobial resistance has led to a resurgence of interest in bacteriophage therapies as alternative or adjunctive treatments for bacterial infections. Their therapeutic application is limited, however, by their dependence on predominantly non-essential receptors, enabling bacteria to readily evolve resistance to phage attack. Using an approach analogous to that described for multidrug-resistant Pseudomonas aeruginosa, we aim to exploit this limitation in Mycobacterium tuberculosis (Mtb) by forcing an evolutionary genetic trade-off between acquisition of phage resistance and loss of critical outer membrane components by identifying mycobacteriophages targeting receptors whose loss might potentiate antibiotic activity. 

The efflux pump EfpA has been shown to be upregulated in drug-resistant clinical isolates of Mtb, and is the target of potent antitubercular compounds in preclinical development. Despite being essential for growth of MtbefpA is dispensable in M. smegmatis, enabling us to devise a screening strategy for identifying EfpA-binding mycobacteriophages by testing efpA mutants for resistance to phages that lyse wildtype. Using this approach, environmental samples can be rapidly screened to identify mycobacteriophages utilising EfpA as a binding receptor, which can then be further evaluated for their ability to infect and kill Mtb

Although modern phage therapy remains in its infancy, the recent successful use of mycobacteriophages for treatment of incurable M. abscessus infections validates their therapeutic utility, and the identification of therapies where bacteriophages exert selection for MDR bacteria to become increasingly sensitised to traditional antibiotics could extend the lifetimes of currently available treatments and reduce the emergence of antibiotic resistant infections. 

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