Cargando…

Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis

The approval of bedaquiline has placed energy metabolism in the limelight as an attractive target space for tuberculosis antibiotic development. While bedaquiline inhibits the mycobacterial F(1)F(0) ATP synthase, small molecules targeting other components of the oxidative phosphorylation pathway hav...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, Bei Shi, Hards, Kiel, Engelhart, Curtis A, Hasenoehrl, Erik J, Kalia, Nitin P, Mackenzie, Jared S, Sviriaeva, Ekaterina, Chong, Shi Min Sherilyn, Manimekalai, Malathy Sony S, Koh, Vanessa H, Chan, John, Xu, Jiayong, Alonso, Sylvie, Miller, Marvin J, Steyn, Adrie J C, Grüber, Gerhard, Schnappinger, Dirk, Berney, Michael, Cook, Gregory M, Moraski, Garrett C, Pethe, Kevin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799364/
https://www.ncbi.nlm.nih.gov/pubmed/33283973
http://dx.doi.org/10.15252/emmm.202013207
_version_ 1783635119930605568
author Lee, Bei Shi
Hards, Kiel
Engelhart, Curtis A
Hasenoehrl, Erik J
Kalia, Nitin P
Mackenzie, Jared S
Sviriaeva, Ekaterina
Chong, Shi Min Sherilyn
Manimekalai, Malathy Sony S
Koh, Vanessa H
Chan, John
Xu, Jiayong
Alonso, Sylvie
Miller, Marvin J
Steyn, Adrie J C
Grüber, Gerhard
Schnappinger, Dirk
Berney, Michael
Cook, Gregory M
Moraski, Garrett C
Pethe, Kevin
author_facet Lee, Bei Shi
Hards, Kiel
Engelhart, Curtis A
Hasenoehrl, Erik J
Kalia, Nitin P
Mackenzie, Jared S
Sviriaeva, Ekaterina
Chong, Shi Min Sherilyn
Manimekalai, Malathy Sony S
Koh, Vanessa H
Chan, John
Xu, Jiayong
Alonso, Sylvie
Miller, Marvin J
Steyn, Adrie J C
Grüber, Gerhard
Schnappinger, Dirk
Berney, Michael
Cook, Gregory M
Moraski, Garrett C
Pethe, Kevin
author_sort Lee, Bei Shi
collection PubMed
description The approval of bedaquiline has placed energy metabolism in the limelight as an attractive target space for tuberculosis antibiotic development. While bedaquiline inhibits the mycobacterial F(1)F(0) ATP synthase, small molecules targeting other components of the oxidative phosphorylation pathway have been identified. Of particular interest is Telacebec (Q203), a phase 2 drug candidate inhibitor of the cytochrome bcc:aa(3) terminal oxidase. A functional redundancy between the cytochrome bcc:aa(3) and the cytochrome bd oxidase protects M. tuberculosis from Q203‐induced death, highlighting the attractiveness of the bd‐type terminal oxidase for drug development. Here, we employed a facile whole‐cell screen approach to identify the cytochrome bd inhibitor ND‐011992. Although ND‐011992 is ineffective on its own, it inhibits respiration and ATP homeostasis in combination with Q203. The drug combination was bactericidal against replicating and antibiotic‐tolerant, non‐replicating mycobacteria, and increased efficacy relative to that of a single drug in a mouse model. These findings suggest that a cytochrome bd oxidase inhibitor will add value to a drug combination targeting oxidative phosphorylation for tuberculosis treatment.
format Online
Article
Text
id pubmed-7799364
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-77993642021-01-15 Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis Lee, Bei Shi Hards, Kiel Engelhart, Curtis A Hasenoehrl, Erik J Kalia, Nitin P Mackenzie, Jared S Sviriaeva, Ekaterina Chong, Shi Min Sherilyn Manimekalai, Malathy Sony S Koh, Vanessa H Chan, John Xu, Jiayong Alonso, Sylvie Miller, Marvin J Steyn, Adrie J C Grüber, Gerhard Schnappinger, Dirk Berney, Michael Cook, Gregory M Moraski, Garrett C Pethe, Kevin EMBO Mol Med Articles The approval of bedaquiline has placed energy metabolism in the limelight as an attractive target space for tuberculosis antibiotic development. While bedaquiline inhibits the mycobacterial F(1)F(0) ATP synthase, small molecules targeting other components of the oxidative phosphorylation pathway have been identified. Of particular interest is Telacebec (Q203), a phase 2 drug candidate inhibitor of the cytochrome bcc:aa(3) terminal oxidase. A functional redundancy between the cytochrome bcc:aa(3) and the cytochrome bd oxidase protects M. tuberculosis from Q203‐induced death, highlighting the attractiveness of the bd‐type terminal oxidase for drug development. Here, we employed a facile whole‐cell screen approach to identify the cytochrome bd inhibitor ND‐011992. Although ND‐011992 is ineffective on its own, it inhibits respiration and ATP homeostasis in combination with Q203. The drug combination was bactericidal against replicating and antibiotic‐tolerant, non‐replicating mycobacteria, and increased efficacy relative to that of a single drug in a mouse model. These findings suggest that a cytochrome bd oxidase inhibitor will add value to a drug combination targeting oxidative phosphorylation for tuberculosis treatment. John Wiley and Sons Inc. 2020-12-07 2021-01-11 /pmc/articles/PMC7799364/ /pubmed/33283973 http://dx.doi.org/10.15252/emmm.202013207 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Lee, Bei Shi
Hards, Kiel
Engelhart, Curtis A
Hasenoehrl, Erik J
Kalia, Nitin P
Mackenzie, Jared S
Sviriaeva, Ekaterina
Chong, Shi Min Sherilyn
Manimekalai, Malathy Sony S
Koh, Vanessa H
Chan, John
Xu, Jiayong
Alonso, Sylvie
Miller, Marvin J
Steyn, Adrie J C
Grüber, Gerhard
Schnappinger, Dirk
Berney, Michael
Cook, Gregory M
Moraski, Garrett C
Pethe, Kevin
Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis
title Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis
title_full Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis
title_fullStr Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis
title_full_unstemmed Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis
title_short Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis
title_sort dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant mycobacterium tuberculosis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799364/
https://www.ncbi.nlm.nih.gov/pubmed/33283973
http://dx.doi.org/10.15252/emmm.202013207
work_keys_str_mv AT leebeishi dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT hardskiel dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT engelhartcurtisa dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT hasenoehrlerikj dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT kalianitinp dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT mackenziejareds dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT sviriaevaekaterina dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT chongshiminsherilyn dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT manimekalaimalathysonys dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT kohvanessah dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT chanjohn dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT xujiayong dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT alonsosylvie dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT millermarvinj dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT steynadriejc dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT grubergerhard dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT schnappingerdirk dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT berneymichael dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT cookgregorym dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT moraskigarrettc dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis
AT pethekevin dualinhibitionoftheterminaloxidaseseradicatesantibiotictolerantmycobacteriumtuberculosis