Inhaled bacteriophage-loaded polymeric microparticles ameliorate acute lung infections

Abstract

Lung infections associated with pneumonia, or cystic fibrosis caused by Pseudomonas aeruginosa or other bacteria, result in significant morbidity and mortality, in part owing to the development of multidrug resistance, also against last-resort antibiotics. Lytic bacteriophages (that is, viruses that specifically kill bacteria) can reduce lung-associated infections, yet their clinical use is hindered by difficulties in delivering active phages to the deep lung. Here, we show that phage-loaded polymeric microparticles deposit throughout the lung via dry powder inhalation and that they deliver active phages. Phage-loaded microparticles effectively reduced P. aeruginosa infections and the associated inflammation in wild-type and cystic fibrosis transmembrane-conductance-regulator knockout mice, and rescued the mice from pneumonia-associated death. These polymeric microparticles might constitute a clinically translatable therapy for eradicating hospital-acquired lung infections and infections associated with cystic fibrosis.

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Fig. 1: Porous MPs deliver active phages and are effective against P. aeruginosa.
Fig. 2: Phage-MPs are effective against P. aeruginosa biofilms.
Fig. 3: Dry powder formulations of porous MPs for lung delivery.
Fig. 4: Phage-loaded porous MPs reduce bacteria in the lungs of mice.
Fig. 5: Phage-loaded porous MPs reduce bacteria in the lungs of CFKO mice.
Fig. 6: Phage-MPs significantly reduce infection by a clinically derived strain of bacteria in wild-type mice.
Fig. 7: Pretreatment with phage-MPs does not reduce the functional efficacy of the treatment in clearing bacteria from mouse lungs.

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Acknowledgements

This work was funded by the National Institutes of Health (R01 AR062920 (to A.J.G.), F30 AR069472 (to C.T.J.) and S10 OD016264 (to A.J.G.) and a research partnership between Children’s Healthcare of Atlanta and the Georgia Institute of Technology. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Centers for Disease Control and Prevention. Use of trade names and commercial sources is for identification only and does not imply endorsement by the Public Health Service or the US Department of Health and Human Services. We thank R. Hunt for advice and discussions over the course of the project. We also thank DFE Pharma for providing inhalation grade lactose Respitose ML006. Clinical strains were obtained from the Clinical and Translational Research Core of the CF@LANTA RDP Center, funded by the Cystic Fibrosis Foundation (MCCART15R0). PA103 was a gift from J. Goldberg at Emory University.

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R.A., C.T.J., R.M.D., N.A.M. and A.J.G conceived and designed the experiments. R.A., C.T.J. and B.R.I. performed all the experiments. R.M.D. provided phage samples and advice on their use. B.R.I. and N.A.M. handled the cystic fibrosis knockout mice breeding, testing and care. The manuscript was written by R.A., N.A.M. and A.J.G. All authors discussed the results and reviewed the manuscript.

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Correspondence to Andrés J. García.

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Agarwal, R., Johnson, C.T., Imhoff, B.R. et al. Inhaled bacteriophage-loaded polymeric microparticles ameliorate acute lung infections. Nat Biomed Eng 2, 841–849 (2018). https://doi.org/10.1038/s41551-018-0263-5

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