Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish
Pulmonary infections caused by Mycobacterium abscessus are emerging as a global threat, especially in cystic fibrosis patients. Further intensifying the concern of M. abscessus infection is the recent evidence of human-to-human transmission of the infection. M. abscessus is a naturally multidrug-res...
| Main Authors: | , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2018
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| Online Access: | https://hdl.handle.net/10356/87225 http://hdl.handle.net/10220/44362 |
| _version_ | 1826129643743215616 |
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| author | Dupont, Christian Viljoen, Albertus Thomas, Sangeeta Roquet-Banères, Françoise Herrmann, Jean-Louis Pethe, Kevin Kremer, Laurent |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Dupont, Christian Viljoen, Albertus Thomas, Sangeeta Roquet-Banères, Françoise Herrmann, Jean-Louis Pethe, Kevin Kremer, Laurent |
| author_sort | Dupont, Christian |
| collection | NTU |
| description | Pulmonary infections caused by Mycobacterium abscessus are emerging as a global threat, especially in cystic fibrosis patients. Further intensifying the concern of M. abscessus infection is the recent evidence of human-to-human transmission of the infection. M. abscessus is a naturally multidrug-resistant fast-growing pathogen for which pharmacological options are limited. Repurposing antitubercular drugs represents an attractive option for the development of chemotherapeutic alternatives against M. abscessus infections. Bedaquiline (BDQ), an ATP synthase inhibitor, has recently been approved for the treatment of multidrug-resistant tuberculosis. Herein, we show that BDQ has a very low MIC against a vast panel of clinical isolates. Despite being bacteriostatic in vitro, BDQ was highly efficacious in a zebrafish model of M. abscessus infection. Remarkably, a very short period of treatment was sufficient to protect the infected larvae from M. abscessus-induced killing. This was corroborated with reduced numbers of abscesses and cords, considered to be major pathophysiological signs in infected zebrafish. Mode-of-action studies revealed that BDQ triggered a rapid depletion of ATP in M. abscessus in vitro, consistent with the drug targeting the FoF1 ATP synthase. Importantly, despite a failure to select in vitro for spontaneous mutants that are highly resistant to BDQ, the transfer of single nucleotide polymorphisms leading to D29V or A64P substitutions in atpE conferred high resistance, thus resolving the target of BDQ in M. abscessus. Overall, this study indicates that BDQ is active against M. abscessus in vitro and in vivo and should be considered for clinical use against the difficult-to-manage M. abscessus pulmonary infections. |
| first_indexed | 2024-10-01T07:43:53Z |
| format | Journal Article |
| id | ntu-10356/87225 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:43:53Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | ntu-10356/872252020-11-01T05:28:54Z Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish Dupont, Christian Viljoen, Albertus Thomas, Sangeeta Roquet-Banères, Françoise Herrmann, Jean-Louis Pethe, Kevin Kremer, Laurent School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) Bedaquiline Zebrafish Pulmonary infections caused by Mycobacterium abscessus are emerging as a global threat, especially in cystic fibrosis patients. Further intensifying the concern of M. abscessus infection is the recent evidence of human-to-human transmission of the infection. M. abscessus is a naturally multidrug-resistant fast-growing pathogen for which pharmacological options are limited. Repurposing antitubercular drugs represents an attractive option for the development of chemotherapeutic alternatives against M. abscessus infections. Bedaquiline (BDQ), an ATP synthase inhibitor, has recently been approved for the treatment of multidrug-resistant tuberculosis. Herein, we show that BDQ has a very low MIC against a vast panel of clinical isolates. Despite being bacteriostatic in vitro, BDQ was highly efficacious in a zebrafish model of M. abscessus infection. Remarkably, a very short period of treatment was sufficient to protect the infected larvae from M. abscessus-induced killing. This was corroborated with reduced numbers of abscesses and cords, considered to be major pathophysiological signs in infected zebrafish. Mode-of-action studies revealed that BDQ triggered a rapid depletion of ATP in M. abscessus in vitro, consistent with the drug targeting the FoF1 ATP synthase. Importantly, despite a failure to select in vitro for spontaneous mutants that are highly resistant to BDQ, the transfer of single nucleotide polymorphisms leading to D29V or A64P substitutions in atpE conferred high resistance, thus resolving the target of BDQ in M. abscessus. Overall, this study indicates that BDQ is active against M. abscessus in vitro and in vivo and should be considered for clinical use against the difficult-to-manage M. abscessus pulmonary infections. NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore) Published version 2018-02-01T04:23:32Z 2019-12-06T16:37:37Z 2018-02-01T04:23:32Z 2019-12-06T16:37:37Z 2017 Journal Article Dupont, C., Viljoen, A., Thomas, S., Roquet-Banères, F., Herrmann, J. L., Pethe, K., et al. (2017). Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish. Antimicrobial Agents and Chemotherapy, 61(11), e01225-17-. 0066-4804 https://hdl.handle.net/10356/87225 http://hdl.handle.net/10220/44362 10.1128/AAC.01225-17 en Antimicrobial Agents and Chemotherapy © 2017 American Society for Microbiology (ASM). This paper was published in Antimicrobial Agents and Chemotherapy and is made available as an electronic reprint (preprint) with permission of American Society for Microbiology (ASM). The published version is available at: [http://dx.doi.org/10.1128/AAC.01225-17]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law. 15 p. application/pdf |
| spellingShingle | Bedaquiline Zebrafish Dupont, Christian Viljoen, Albertus Thomas, Sangeeta Roquet-Banères, Françoise Herrmann, Jean-Louis Pethe, Kevin Kremer, Laurent Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish |
| title | Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish |
| title_full | Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish |
| title_fullStr | Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish |
| title_full_unstemmed | Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish |
| title_short | Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish |
| title_sort | bedaquiline inhibits the atp synthase in mycobacterium abscessus and is effective in infected zebrafish |
| topic | Bedaquiline Zebrafish |
| url | https://hdl.handle.net/10356/87225 http://hdl.handle.net/10220/44362 |
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