| Autor: |
Sue C. Nang, Jing Lu, Heidi H. Yu, Hasini Wickremasinghe, Mohammad A. K. Azad, Meiling Han, Jinxin Zhao, Gauri Rao, Phillip J. Bergen, Tony Velkov, Norelle Sherry, David T. McCarthy, Saima Aslam, Robert T. Schooley, Benjamin P. Howden, Jeremy J. Barr, Yan Zhu, Jian Li |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.11.14.516531 |
| Popis: |
Phage therapy is a promising alternative treatment for multidrug-resistant bacterial infections. Unfortunately, phage resistance represents a major barrier hindering the clinical utility. Mechanistic insights into bacterial phage defense mechanisms are critical to optimize phages therapy. Here, we discovered a repertoire of phage resistance mechanisms in a model strainKlebsiella pneumoniaeMKP103, including the disruption of phage binding site (fhuA::Tn andtonB::Tn), extension of phage latent period (mnmE::Tn andrpoN::Tn) and increased mutation frequency (mutS::Tn andmutL::Tn). Different from the prevailing view that phage resistance re-sensitizes antibiotic-resistant bacteria, we demonstrated a bi-directional steering effect on antibiotic susceptibility. Specifically, it was uncovered that, whilerpoN::Tn became more susceptible to colistin,mutS::Tn andmutL::Tn caused increased resistance to rifampicin and the last-line colistin. Our findings highlight the diversified strategies utilized byK. pneumoniaeto overcome phage infection. Overall, mechanism-guided phage steering represents a vital strategy to maximize the success of phage therapy. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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