The association between sterilizing activity and drug distribution into tuberculosis lesions

Brendan Prideaux; Laura E. Via; Matthew D. Zimmerman; Seokyong Eum; Jansy Sarathy; Paul O'Brien; Chao Chen; Firat Kaya; Danielle M. Weiner; Pei Yu Chen; Taeksun Song; Myungsun Lee; Tae Sun Shim; Jeong Su Cho; Wooshik Kim; Sang Nae Cho; Kenneth N. Olivier; Clifton E. Barry; Véronique Dartois

doi:10.1038/nm.3937

The association between sterilizing activity and drug distribution into tuberculosis lesions

Brendan Prideaux, Laura E. Via, Matthew D. Zimmerman, Seokyong Eum, Jansy Sarathy, Paul O'Brien, Chao Chen, Firat Kaya, Danielle M. Weiner, Pei Yu Chen, Taeksun Song, Myungsun Lee, Tae Sun Shim, Jeong Su Cho, Wooshik Kim, Sang Nae Cho, Kenneth N. Olivier, Clifton E. Barry, Véronique Dartois

Department of Microbiology

Research output: Contribution to journal › Article › peer-review

317 Citations (Scopus)

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 reside. 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 mice, 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.

Original language	English
Pages (from-to)	1223-1227
Number of pages	5
Journal	Nature Medicine
Volume	21
Issue number	10
DOIs	https://doi.org/10.1038/nm.3937
Publication status	Published - 2015 Oct 1

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.

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Biochemistry, Genetics and Molecular Biology(all)

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10.1038/nm.3937

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Prideaux, B., Via, L. E., Zimmerman, M. D., Eum, S., Sarathy, J., O'Brien, P., Chen, C., Kaya, F., Weiner, D. M., Chen, P. Y., Song, T., Lee, M., Shim, T. S., Cho, J. S., Kim, W., Cho, S. N., Olivier, K. N., Barry, C. E., & Dartois, V. (2015). The association between sterilizing activity and drug distribution into tuberculosis lesions. Nature Medicine, 21(10), 1223-1227. https://doi.org/10.1038/nm.3937

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title = "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 reside. 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 mice, 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.",

author = "Brendan Prideaux and Via, {Laura E.} and Zimmerman, {Matthew D.} and Seokyong Eum and Jansy Sarathy and Paul O'Brien and Chao Chen and Firat Kaya and Weiner, {Danielle M.} and Chen, {Pei Yu} and Taeksun Song and Myungsun Lee and Shim, {Tae Sun} and Cho, {Jeong Su} and Wooshik Kim and Cho, {Sang Nae} and Olivier, {Kenneth N.} and Barry, {Clifton E.} and V{\'e}ronique Dartois",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2015 Nature America, Inc. All rights reserved.",

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Prideaux, B, Via, LE, Zimmerman, MD, Eum, S, Sarathy, J, O'Brien, P, Chen, C, Kaya, F, Weiner, DM, Chen, PY, Song, T, Lee, M, Shim, TS, Cho, JS, Kim, W, Cho, SN, Olivier, KN, Barry, CE & Dartois, V 2015, 'The association between sterilizing activity and drug distribution into tuberculosis lesions', Nature Medicine, vol. 21, no. 10, pp. 1223-1227. https://doi.org/10.1038/nm.3937

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AU - Prideaux, Brendan

AU - Via, Laura E.

AU - Zimmerman, Matthew D.

AU - Eum, Seokyong

AU - Sarathy, Jansy

AU - O'Brien, Paul

AU - Chen, Chao

AU - Kaya, Firat

AU - Weiner, Danielle M.

AU - Chen, Pei Yu

AU - Song, Taeksun

AU - Lee, Myungsun

AU - Shim, Tae Sun

AU - Cho, Jeong Su

AU - Kim, Wooshik

AU - Cho, Sang Nae

AU - Olivier, Kenneth N.

AU - Barry, Clifton E.

AU - Dartois, Véronique

N1 - Funding Information: 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. Publisher Copyright: © 2015 Nature America, Inc. All rights reserved.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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 reside. 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 mice, 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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The association between sterilizing activity and drug distribution into tuberculosis lesions

Abstract

Bibliographical note

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UN SDGs

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