Diversified repertoire of phage defenses in Klebsiella pneumoniae: Bi-directional steering effects impacting antibiotic susceptibility

Nang, S. C.; Lu, J.; Yu, H.; Wickremasinghe, H.; Azad, M. A. K.; Han, M.; Zhao, J.; Rao, G.; Bergen, P. J.; Velkov, T.; Sherry, N.; McCarthy, D. T.; Aslam, S.; Schooley, R. T.; Howden, B. P.; Barr, J. J.; Zhu, Y.; Li, J.

doi:10.1101/2022.11.14.516531

bioRxiv · 10.1101/2022.11.14.516531

Diversified repertoire of phage defenses in Klebsiella pneumoniae: Bi-directional steering effects impacting antibiotic susceptibility

Nang, S. C.·Lu, J.·Yu, H.·Wickremasinghe, H.·Azad, M. A. K.·Han, M.·Zhao, J.·Rao, G.·Bergen, P. J.·Velkov, T.·Sherry, N.·McCarthy, D. T.·Aslam, S.·Schooley, R. T.·Howden, B. P.·Barr, J. J.·Zhu, Y.·Li, J.

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Abstract

Bacteriophage (phage) therapy is rising as a promising anti-infective option to combat antimicrobial resistance; however, its clinical utilization is severely hindered by the potential emergence of phage resistance. Fortunately, certain phage resistance mechanisms can restore bacterial antibiotic susceptibility, making the combination of phages with antibiotics a potential strategic approach. Here, we demonstrated that phage resistance can also lead to increased antibiotic resistance and provided mechanistic insights into bacterial phage defense mechanisms. We discovered a repertoire of phage resistance mechanisms in Klebsiella pneumoniae, including the disruption of phage binding site (fhuA::Tn and tonB::Tn), extension of phage latent period (mnmE::Tn and rpoN::Tn) and increased mutation frequency (mutS::Tn and mutL::Tn). Different from the prevailing view that phage resistance re-sensitizes antibiotic-resistant bacteria, we revealed a bidirectional steering effect on the bacterial antibiotic susceptibility. Specifically, it was uncovered that, while rpoN::Tn became more susceptible to colistin, mutS::Tn and mutL::Tn caused increased resistance to rifampicin and colistin. Our findings highlight the diversified strategies utilized by K. pneumoniae to overcome phage infection and the parallel effect on the antibiotic susceptibility. Mechanism-guided phage steering represents a rational strategy that should be incorporated into phage therapy to better inform clinical decisions.

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Nang, S. C., Lu, J., Yu, H., Wickremasinghe, H., Azad, M. A. K., Han, M., Zhao, J., Rao, G., Bergen, P. J., Velkov, T., Sherry, N., McCarthy, D. T., Aslam, S., Schooley, R. T., Howden, B. P., Barr, J. J., Zhu, Y., Li, J.. 2022-11-15. Diversified repertoire of phage defenses in Klebsiella pneumoniae: Bi-directional steering effects impacting antibiotic susceptibility. https://doi.org/10.1101/2022.11.14.516531

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