Carbon metabolism modulates the efficacy of drugs targeting the cytochrome bc1:aa3 in Mycobacterium tuberculosis
The influence of carbon metabolism on oxidative phosphorylation is poorly understood in mycobacteria. M. tuberculosis expresses two respiratory terminal oxidases, the cytochrome bc1:aa3 and the cytochrome bd oxidase, which are jointly required for oxidative phosphorylation and mycobacterial viabilit...
| Main Authors: | , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2019
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| Online Access: | https://hdl.handle.net/10356/89857 http://hdl.handle.net/10220/49328 |
| _version_ | 1826122306749988864 |
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| author | Moraski, Garrett C. Miller, Marvin J. Pethe, Kevin Kalia, Nitin Pal Lee, Bei Shi Nurlilah Ab Rahman |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Moraski, Garrett C. Miller, Marvin J. Pethe, Kevin Kalia, Nitin Pal Lee, Bei Shi Nurlilah Ab Rahman |
| author_sort | Moraski, Garrett C. |
| collection | NTU |
| description | The influence of carbon metabolism on oxidative phosphorylation is poorly understood in mycobacteria. M. tuberculosis expresses two respiratory terminal oxidases, the cytochrome bc1:aa3 and the cytochrome bd oxidase, which are jointly required for oxidative phosphorylation and mycobacterial viability. The essentiality of the cytochrome bc1:aa3 for optimum growth is illustrated by its vulnerability to chemical inhibition by the clinical drug candidate Q203 and several other chemical series. The cytochrome bd oxidase is not strictly essential for growth but is required to maintain bioenergetics when the function of the cytochrome bc1:aa3 is compromised. In this study, we observed that the potency of drugs targeting the cytochrome bc1:aa3 is influenced by carbon metabolism. The efficacy of Q203 and related derivatives was alleviated by glycerol supplementation. The negative effect of glycerol supplementation on Q203 potency correlated with an upregulation of the cytochrome bd oxidase-encoding cydABDC operon. Upon deletion of cydAB, the detrimental effect of glycerol on the potency of Q203 was abrogated. The same phenomenon was also observed in recent clinical isolates, but to a lesser extent compared to the laboratory-adapted strain H37Rv. This study reinforces the importance of optimizing in vitro culture conditions for drug evaluation in mycobacteria, a factor which appeared to be particularly essential for drugs targeting the cytochrome bc1:aa3 terminal oxidase. |
| first_indexed | 2024-10-01T05:46:20Z |
| format | Journal Article |
| id | ntu-10356/89857 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:46:20Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-10356/898572020-11-01T05:21:39Z Carbon metabolism modulates the efficacy of drugs targeting the cytochrome bc1:aa3 in Mycobacterium tuberculosis Moraski, Garrett C. Miller, Marvin J. Pethe, Kevin Kalia, Nitin Pal Lee, Bei Shi Nurlilah Ab Rahman School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) Tuberculosis Antimicrobials Science::Chemistry The influence of carbon metabolism on oxidative phosphorylation is poorly understood in mycobacteria. M. tuberculosis expresses two respiratory terminal oxidases, the cytochrome bc1:aa3 and the cytochrome bd oxidase, which are jointly required for oxidative phosphorylation and mycobacterial viability. The essentiality of the cytochrome bc1:aa3 for optimum growth is illustrated by its vulnerability to chemical inhibition by the clinical drug candidate Q203 and several other chemical series. The cytochrome bd oxidase is not strictly essential for growth but is required to maintain bioenergetics when the function of the cytochrome bc1:aa3 is compromised. In this study, we observed that the potency of drugs targeting the cytochrome bc1:aa3 is influenced by carbon metabolism. The efficacy of Q203 and related derivatives was alleviated by glycerol supplementation. The negative effect of glycerol supplementation on Q203 potency correlated with an upregulation of the cytochrome bd oxidase-encoding cydABDC operon. Upon deletion of cydAB, the detrimental effect of glycerol on the potency of Q203 was abrogated. The same phenomenon was also observed in recent clinical isolates, but to a lesser extent compared to the laboratory-adapted strain H37Rv. This study reinforces the importance of optimizing in vitro culture conditions for drug evaluation in mycobacteria, a factor which appeared to be particularly essential for drugs targeting the cytochrome bc1:aa3 terminal oxidase. NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore) Published version 2019-07-12T05:17:20Z 2019-12-06T17:35:10Z 2019-07-12T05:17:20Z 2019-12-06T17:35:10Z 2019 Journal Article Kalia, N. P., Lee, B. S., Nurlilah Ab Rahman, Moraski, G. C., Miller, M. J., & Pethe, K. (2019). Carbon metabolism modulates the efficacy of drugs targeting the cytochrome bc1:aa3 in Mycobacterium tuberculosis. Scientific Reports, 9(1), 8608-. doi:10.1038/s41598-019-44887-9 https://hdl.handle.net/10356/89857 http://hdl.handle.net/10220/49328 10.1038/s41598-019-44887-9 en Scientific Reports © 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. 9 p. application/pdf |
| spellingShingle | Tuberculosis Antimicrobials Science::Chemistry Moraski, Garrett C. Miller, Marvin J. Pethe, Kevin Kalia, Nitin Pal Lee, Bei Shi Nurlilah Ab Rahman Carbon metabolism modulates the efficacy of drugs targeting the cytochrome bc1:aa3 in Mycobacterium tuberculosis |
| title | Carbon metabolism modulates the efficacy of drugs targeting the cytochrome bc1:aa3 in Mycobacterium tuberculosis |
| title_full | Carbon metabolism modulates the efficacy of drugs targeting the cytochrome bc1:aa3 in Mycobacterium tuberculosis |
| title_fullStr | Carbon metabolism modulates the efficacy of drugs targeting the cytochrome bc1:aa3 in Mycobacterium tuberculosis |
| title_full_unstemmed | Carbon metabolism modulates the efficacy of drugs targeting the cytochrome bc1:aa3 in Mycobacterium tuberculosis |
| title_short | Carbon metabolism modulates the efficacy of drugs targeting the cytochrome bc1:aa3 in Mycobacterium tuberculosis |
| title_sort | carbon metabolism modulates the efficacy of drugs targeting the cytochrome bc1 aa3 in mycobacterium tuberculosis |
| topic | Tuberculosis Antimicrobials Science::Chemistry |
| url | https://hdl.handle.net/10356/89857 http://hdl.handle.net/10220/49328 |
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