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The association between sterilizing activity and drug distribution into tuberculosis lesions

Abstract

Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside1. In contrast, moxifloxacin, which is active in vitro against a subpopulation of Mycobacterium tuberculosis that persists in specific niches under drug pressure and has achieved treatment shortening in mice2, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug-resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration may contribute to treatment outcome has wide implications for TB.

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Figure 1: Quantitative drug distribution in human pulmonary lesions.
Figure 2: Two-dimensional imaging of MXF and PZA by MALDI mass spectrometry.
Figure 3: Penetration of RIF in TB lesions.
Figure 4: Factors affecting drug diffusion into caseum.

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Acknowledgements

We thank D. Young and the funders of the Grand Challenge for Global Health (GCGH 11) consortium for their faith and support. We are grateful to the subjects who enrolled in the study; Y. Kim, M.S. Kong, Y. Cai, J. Gonzales and L. Goldfeder; and the clinical teams at the three Korean centers (Asan Medical Centre, Pusan National University Hospital, and the National Medical Center) for their efforts in making the study a success. We thank S. Dorman, D. Alland and H. Boshoff for sharing clinical MIC and in vitro MAC data sets, M. Stoeckli and D. Staab for providing access to the MALDI imaging platform at the Novartis Institutes for Biomedical Research, E. Eugenin, J. Flynn and J. Mattila for sharing images of M. tuberculosis in nonhuman primate lesions, and T. Dick for discussions and advice. This work was carried out with funding from US National Institutes of Health (NIH) grant 1R01AI106398-01 (V.D.), grant OPP1066499 (V.D.) from the Bill and Melinda Gates Foundation, the Intramural Research Program of the NIH National Institute of Allergy and Infectious Diseases (C.E.B.) and the National Heart, Lung and Blood Institute (K.N.O.), as well as funding from the Korean Centers for Disease Control of the Korean Ministry of Health and Welfare to the International Tuberculosis Research Center.

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Authors and Affiliations

Authors

Contributions

B.P. and P.-Y.C. developed all MALDI MSI methods and imaged the study drugs in lung biopsies; L.E.V., C.E.B., S.N.C. and V.D. conceived the study and wrote the clinical protocol; L.E.V. and S.E. developed the dissection protocol and conducted lung dissections; M.D.Z. and F.K. quantified all study drugs in plasma, lung and lesions; J.S., P.O'B., D.M.W. and F.K. developed methods to sterilize TB-infected samples and extract the study drugs; J.S. and C.C. developed the caseum binding and macrophage uptake assay and quantified the study drugs; T.S. collated clinical and radiological data and facilitated sample collection and transport; M.L. coordinated patient enrollment, confirmed study eligibility and facilitated case reporting; T.S.S., J.S.C., W.K., S.N.C. and K.N.O. coordinated lung resection surgeries; C.E.B. and V.D. wrote the manuscript.

Corresponding authors

Correspondence to Clifton E Barry III or Véronique Dartois.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12 and Supplementary Tables 1–3 (PDF 2334 kb)

Supplementary Data 1

Concentration of study drugs in plasma (XLSX 28 kb)

Supplementary Data 2

Concentration of study drugs in uninvolved lung (XLSX 31 kb)

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Prideaux, B., Via, L., Zimmerman, M. et al. The association between sterilizing activity and drug distribution into tuberculosis lesions. Nat Med 21, 1223–1227 (2015). https://doi.org/10.1038/nm.3937

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