Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics
Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), still remains one of the leading causes of death from a single infectious agent worldwide. The high prevalence of this disease is mostly ascribed to the rapid development of drug resistance to the cu...
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| Format: | Article |
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MDPI AG
2021-06-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/10/6/693 |
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| author | Kirsten E. Knoll Zander Lindeque Adetomiwa A. Adeniji Carel B. Oosthuizen Namrita Lall Du Toit Loots |
| author_facet | Kirsten E. Knoll Zander Lindeque Adetomiwa A. Adeniji Carel B. Oosthuizen Namrita Lall Du Toit Loots |
| author_sort | Kirsten E. Knoll |
| collection | DOAJ |
| description | Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), still remains one of the leading causes of death from a single infectious agent worldwide. The high prevalence of this disease is mostly ascribed to the rapid development of drug resistance to the current anti-TB drugs, exacerbated by lack of patient adherence due to drug toxicity. The aforementioned highlights the urgent need for new anti-TB compounds with different antimycobacterial mechanisms of action to those currently being used. An <i>N</i>-alkyl quinolone; decoquinate derivative RMB041, has recently shown promising antimicrobial activity against <i>Mtb</i>, while also exhibiting low cytotoxicity and excellent pharmacokinetic characteristics. Its exact mechanism of action, however, is still unknown. Considering this, we used GCxGC-TOFMS and well described metabolomic approaches to analyze and compare the metabolic alterations of <i>Mtb</i> treated with decoquinate derivative RMB041 by comparison to non-treated <i>Mtb</i> controls. The most significantly altered pathways in <i>Mtb</i> treated with this drug include fatty acid metabolism, amino acid metabolism, glycerol metabolism, and the urea cycle. These changes support previous findings suggesting this drug acts primarily on the cell wall and secondarily on the DNA metabolism of <i>Mtb</i>. Additionally, we identified metabolic changes suggesting inhibition of protein synthesis and a state of dormancy. |
| first_indexed | 2024-03-10T10:33:26Z |
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| id | doaj.art-ac6a3b07257046a4bfd2425f6605acb1 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-10T10:33:26Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-ac6a3b07257046a4bfd2425f6605acb12023-11-21T23:29:36ZengMDPI AGAntibiotics2079-63822021-06-0110669310.3390/antibiotics10060693Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using MetabolomicsKirsten E. Knoll0Zander Lindeque1Adetomiwa A. Adeniji2Carel B. Oosthuizen3Namrita Lall4Du Toit Loots5Human Metabolomics, North-West University, Private Bag x6001, Box 269, Potchefstroom 2531, South AfricaHuman Metabolomics, North-West University, Private Bag x6001, Box 269, Potchefstroom 2531, South AfricaHuman Metabolomics, North-West University, Private Bag x6001, Box 269, Potchefstroom 2531, South AfricaDepartment of Plant and Soil Sciences, Faculty of Natural and Agricultural Sciences, University of Pretoria, Pretoria 0002, South AfricaDepartment of Plant and Soil Sciences, Faculty of Natural and Agricultural Sciences, University of Pretoria, Pretoria 0002, South AfricaHuman Metabolomics, North-West University, Private Bag x6001, Box 269, Potchefstroom 2531, South AfricaTuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), still remains one of the leading causes of death from a single infectious agent worldwide. The high prevalence of this disease is mostly ascribed to the rapid development of drug resistance to the current anti-TB drugs, exacerbated by lack of patient adherence due to drug toxicity. The aforementioned highlights the urgent need for new anti-TB compounds with different antimycobacterial mechanisms of action to those currently being used. An <i>N</i>-alkyl quinolone; decoquinate derivative RMB041, has recently shown promising antimicrobial activity against <i>Mtb</i>, while also exhibiting low cytotoxicity and excellent pharmacokinetic characteristics. Its exact mechanism of action, however, is still unknown. Considering this, we used GCxGC-TOFMS and well described metabolomic approaches to analyze and compare the metabolic alterations of <i>Mtb</i> treated with decoquinate derivative RMB041 by comparison to non-treated <i>Mtb</i> controls. The most significantly altered pathways in <i>Mtb</i> treated with this drug include fatty acid metabolism, amino acid metabolism, glycerol metabolism, and the urea cycle. These changes support previous findings suggesting this drug acts primarily on the cell wall and secondarily on the DNA metabolism of <i>Mtb</i>. Additionally, we identified metabolic changes suggesting inhibition of protein synthesis and a state of dormancy.https://www.mdpi.com/2079-6382/10/6/693decoquinate derivative RMB041<i>Mycobacterium tuberculosis</i>tuberculosismetabolomicsGCxGC-TOFMSmechanism of action |
| spellingShingle | Kirsten E. Knoll Zander Lindeque Adetomiwa A. Adeniji Carel B. Oosthuizen Namrita Lall Du Toit Loots Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics Antibiotics decoquinate derivative RMB041 <i>Mycobacterium tuberculosis</i> tuberculosis metabolomics GCxGC-TOFMS mechanism of action |
| title | Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics |
| title_full | Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics |
| title_fullStr | Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics |
| title_full_unstemmed | Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics |
| title_short | Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics |
| title_sort | elucidating the antimycobacterial mechanism of action of decoquinate derivative rmb041 using metabolomics |
| topic | decoquinate derivative RMB041 <i>Mycobacterium tuberculosis</i> tuberculosis metabolomics GCxGC-TOFMS mechanism of action |
| url | https://www.mdpi.com/2079-6382/10/6/693 |
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