Targeting protein biotinylation enhances tuberculosis chemotherapy

Divya Tiwari; Sae Woong Park; Maram M. Essawy; Surendra Dawadi; Alan Mason; Madhumitha Nandakumar; Matthew Zimmerman; Marizel Mina; Hsin Pin Ho; Curtis A. Engelhart; Thomas Ioerger; James C. Sacchettini; Kyu Rhee; Sabine Ehrt; Courtney C. Aldrich; Véronique Dartois; Dirk Schnappinger

doi:10.1126/scitranslmed.aal1803

Targeting protein biotinylation enhances tuberculosis chemotherapy

Divya Tiwari
, Sae Woong Park
, Maram M. Essawy
, Surendra Dawadi
, Alan Mason
, Madhumitha Nandakumar
, Matthew Zimmerman
, Marizel Mina
, Hsin Pin Ho
, Curtis A. Engelhart
, Thomas Ioerger
, James C. Sacchettini
, Kyu Rhee
, Sabine Ehrt
, Courtney C. Aldrich
, Véronique Dartois
, Dirk Schnappinger

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

31 Scopus citations

Abstract

Successful drug treatment for tuberculosis (TB) depends on the unique contributions of its component drugs. Drug resistance poses a threat to the efficacy of individual drugs and the regimens to which they contribute. Biologically and chemically validated targets capable of replacing individual components of current TB chemotherapy are a major unmet need in TB drug development. We demonstrate that chemical inhibition of the bacterial biotin protein ligase (BPL) with the inhibitor Bio-AMS (5′-[N-(d-biotinoyl)sulfamoyl]amino-5′-deoxyadenosine) killed Mycobacterium tuberculosis (Mtb), the bacterial pathogen causing TB. We also show that genetic silencing of BPL eliminated the pathogen efficiently from mice during acute and chronic infection with Mtb. Partial chemical inactivation of BPL increased the potency of two first-line drugs, rifampicin and ethambutol, and genetic interference with protein biotinylation accelerated clearance of Mtb from mouse lungs and spleens by rifampicin. These studies validate BPL as a potential drug target that could serve as an alternate frontline target in the development of new drugs against Mtb.

Original language	English (US)
Article number	eaal1803
Journal	Science Translational Medicine
Volume	10
Issue number	438
DOIs	https://doi.org/10.1126/scitranslmed.aal1803
State	Published - Apr 25 2018

Bibliographical note

Funding Information:
This work was supported by grant #AI091790 [National Institute of Allergy and Infectious Diseases (NIAID)] to D.S. and C.C.A., #U19AI111143 (Tri-Institutional TB Research Unit, part of the NIAID Tuberculosis Research Units Network) to D.S. and V.D., a chair from Welch foundation (A-0015) to J.C.S., and #OPP1154895 from the Bill and Melinda Gates Foundation to V.D. and D.S.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Tiwari, D., Park, S. W., Essawy, M. M., Dawadi, S., Mason, A., Nandakumar, M., Zimmerman, M., Mina, M., Ho, H. P., Engelhart, C. A., Ioerger, T., Sacchettini, J. C., Rhee, K., Ehrt, S., Aldrich, C. C., Dartois, V., & Schnappinger, D. (2018). Targeting protein biotinylation enhances tuberculosis chemotherapy. Science Translational Medicine, 10(438), Article eaal1803. https://doi.org/10.1126/scitranslmed.aal1803

Tiwari, D, Park, SW, Essawy, MM, Dawadi, S, Mason, A, Nandakumar, M, Zimmerman, M, Mina, M, Ho, HP, Engelhart, CA, Ioerger, T, Sacchettini, JC, Rhee, K, Ehrt, S, Aldrich, CC, Dartois, V & Schnappinger, D 2018, 'Targeting protein biotinylation enhances tuberculosis chemotherapy', Science Translational Medicine, vol. 10, no. 438, eaal1803. https://doi.org/10.1126/scitranslmed.aal1803

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abstract = "Successful drug treatment for tuberculosis (TB) depends on the unique contributions of its component drugs. Drug resistance poses a threat to the efficacy of individual drugs and the regimens to which they contribute. Biologically and chemically validated targets capable of replacing individual components of current TB chemotherapy are a major unmet need in TB drug development. We demonstrate that chemical inhibition of the bacterial biotin protein ligase (BPL) with the inhibitor Bio-AMS (5′-[N-(d-biotinoyl)sulfamoyl]amino-5′-deoxyadenosine) killed Mycobacterium tuberculosis (Mtb), the bacterial pathogen causing TB. We also show that genetic silencing of BPL eliminated the pathogen efficiently from mice during acute and chronic infection with Mtb. Partial chemical inactivation of BPL increased the potency of two first-line drugs, rifampicin and ethambutol, and genetic interference with protein biotinylation accelerated clearance of Mtb from mouse lungs and spleens by rifampicin. These studies validate BPL as a potential drug target that could serve as an alternate frontline target in the development of new drugs against Mtb.",

author = "Divya Tiwari and Park, \{Sae Woong\} and Essawy, \{Maram M.\} and Surendra Dawadi and Alan Mason and Madhumitha Nandakumar and Matthew Zimmerman and Marizel Mina and Ho, \{Hsin Pin\} and Engelhart, \{Curtis A.\} and Thomas Ioerger and Sacchettini, \{James C.\} and Kyu Rhee and Sabine Ehrt and Aldrich, \{Courtney C.\} and V{\'e}ronique Dartois and Dirk Schnappinger",

note = "Funding Information: This work was supported by grant \#AI091790 [National Institute of Allergy and Infectious Diseases (NIAID)] to D.S. and C.C.A., \#U19AI111143 (Tri-Institutional TB Research Unit, part of the NIAID Tuberculosis Research Units Network) to D.S. and V.D., a chair from Welch foundation (A-0015) to J.C.S., and \#OPP1154895 from the Bill and Melinda Gates Foundation to V.D. and D.S.",

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AU - Tiwari, Divya

AU - Park, Sae Woong

AU - Essawy, Maram M.

AU - Dawadi, Surendra

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AU - Nandakumar, Madhumitha

AU - Zimmerman, Matthew

AU - Mina, Marizel

AU - Ho, Hsin Pin

AU - Engelhart, Curtis A.

AU - Ioerger, Thomas

AU - Sacchettini, James C.

AU - Rhee, Kyu

AU - Ehrt, Sabine

AU - Aldrich, Courtney C.

AU - Dartois, Véronique

AU - Schnappinger, Dirk

N1 - Funding Information: This work was supported by grant #AI091790 [National Institute of Allergy and Infectious Diseases (NIAID)] to D.S. and C.C.A., #U19AI111143 (Tri-Institutional TB Research Unit, part of the NIAID Tuberculosis Research Units Network) to D.S. and V.D., a chair from Welch foundation (A-0015) to J.C.S., and #OPP1154895 from the Bill and Melinda Gates Foundation to V.D. and D.S.

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N2 - Successful drug treatment for tuberculosis (TB) depends on the unique contributions of its component drugs. Drug resistance poses a threat to the efficacy of individual drugs and the regimens to which they contribute. Biologically and chemically validated targets capable of replacing individual components of current TB chemotherapy are a major unmet need in TB drug development. We demonstrate that chemical inhibition of the bacterial biotin protein ligase (BPL) with the inhibitor Bio-AMS (5′-[N-(d-biotinoyl)sulfamoyl]amino-5′-deoxyadenosine) killed Mycobacterium tuberculosis (Mtb), the bacterial pathogen causing TB. We also show that genetic silencing of BPL eliminated the pathogen efficiently from mice during acute and chronic infection with Mtb. Partial chemical inactivation of BPL increased the potency of two first-line drugs, rifampicin and ethambutol, and genetic interference with protein biotinylation accelerated clearance of Mtb from mouse lungs and spleens by rifampicin. These studies validate BPL as a potential drug target that could serve as an alternate frontline target in the development of new drugs against Mtb.

AB - Successful drug treatment for tuberculosis (TB) depends on the unique contributions of its component drugs. Drug resistance poses a threat to the efficacy of individual drugs and the regimens to which they contribute. Biologically and chemically validated targets capable of replacing individual components of current TB chemotherapy are a major unmet need in TB drug development. We demonstrate that chemical inhibition of the bacterial biotin protein ligase (BPL) with the inhibitor Bio-AMS (5′-[N-(d-biotinoyl)sulfamoyl]amino-5′-deoxyadenosine) killed Mycobacterium tuberculosis (Mtb), the bacterial pathogen causing TB. We also show that genetic silencing of BPL eliminated the pathogen efficiently from mice during acute and chronic infection with Mtb. Partial chemical inactivation of BPL increased the potency of two first-line drugs, rifampicin and ethambutol, and genetic interference with protein biotinylation accelerated clearance of Mtb from mouse lungs and spleens by rifampicin. These studies validate BPL as a potential drug target that could serve as an alternate frontline target in the development of new drugs against Mtb.

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ER -

Targeting protein biotinylation enhances tuberculosis chemotherapy

Abstract

Bibliographical note

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