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Benjamin Chan, Stephanie Mao, Mark Sistrom, John Wertz, Deepak Narayan, Paul E. Turner.
Yale University, New Haven, CT, USA.

Antibiotic resistant bacterial infections contribute significantly to morbidity and mortality in humans. The increasing prevalence of these infections coupled with the lack of viable alternatives has presented a critical need for the development of new strategies for treatment. One alternative may be phage therapy - the therapeutic application of lytic bacteriophages (the viruses of bacteria). Although this approach has its merits, one concern is that phage resistance can evolve as easily as antibiotic resistance, and in both cases there is no guarantee that the resistance would cause a decline in pathogen virulence. That is, resistant bacteria can flourish because the underlying mutations for resistance do not interfere with the mechanisms of virulence. Our approach is to develop Resistance Targeted Antibiotics (RTAs), a new generation of therapeutic phage that specifically bind to the antibiotic resistance factors of their bacterial hosts forcing an evolutionary trade off. When the inevitable evolution of resistance to RTAs occurs, the bacteria must either lose or modify the targeted resistance factor reducing antibiotic resistance. Our initial target bacterium for RTA development is Pseudomonas aeruginosa, an opportunistic pathogen frequently associated immuno-compromised individuals and infamous for intrinsic antibiotic resistance. Though numerous mechanisms are responsible for antibiotic resistance, a significant mechanism associated with resistance to multiple classes of antibiotic is drug efflux by the chromosomally encoded and often redundant Multi-drug efflux pump (Mex) systems. Here we present data suggesting that a bacteriophage (family Myoviridae) acting as a RTA can force an evolutionary trade-off between susceptibility to viral infection and susceptibility to antibiotics effluxed via the mexXY/mexAB-oprM efflux systems. That is, the phage utilizes the outer membrane porin M (OprM) of the tripartite MexXY/AB-OprM efflux system as a receptor binding site. Moreover, we show that combination therapy involving the phage and traditional antibiotics is synergistic, and especially useful for decreasing bacterial population size. Our approach shows that phage binding to known resistance factors can force an evolutionary trade-off, prolonging the ability to use antibiotics of waning effectiveness.

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