Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics

Simple item page
dc.contributor.authorKnoll, Kirsten E
dc.contributor.authorLindeque, Zander
dc.contributor.authorAdeniji, Adetomiwa A
dc.contributor.authorOosthuizen, Carel B
dc.contributor.authorLall, Namrita
dc.contributor.authorLoots, Du Toit
dc.date.accessioned2021-11-24T16:46:50Z
dc.date.available2021-11-24T16:46:50Z
dc.date.issued2021-06-10
dc.date.updated2021-07-08T14:21:55Z
dc.description.abstractTuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), 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 N-alkyl quinolone; decoquinate derivative RMB041, has recently shown promising antimicrobial activity against Mtb, 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 Mtb treated with decoquinate derivative RMB041 by comparison to non-treated Mtb controls. The most significantly altered pathways in Mtb 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 Mtb. Additionally, we identified metabolic changes suggesting inhibition of protein synthesis and a state of dormancy.en_US
dc.identifierdoi: 10.3390/antibiotics10060693
dc.identifier.apacitationKnoll, K. E., Lindeque, Z., Adeniji, A. A., Oosthuizen, C. B., Lall, N., & Loots, D. T. (2021). Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics. <i>Antibiotics</i>, 10(6), 693. http://hdl.handle.net/11427/35365en_ZA
dc.identifier.chicagocitationKnoll, Kirsten E, Zander Lindeque, Adetomiwa A Adeniji, Carel B Oosthuizen, Namrita Lall, and Du Toit Loots "Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics." <i>Antibiotics</i> 10, 6. (2021): 693. http://hdl.handle.net/11427/35365en_ZA
dc.identifier.citationKnoll, K.E., Lindeque, Z., Adeniji, A.A., Oosthuizen, C.B., Lall, N. & Loots, D.T. 2021. Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics. <i>Antibiotics.</i> 10(6):693. http://hdl.handle.net/11427/35365en_ZA
dc.identifier.ris TY - Journal Article AU - Knoll, Kirsten E AU - Lindeque, Zander AU - Adeniji, Adetomiwa A AU - Oosthuizen, Carel B AU - Lall, Namrita AU - Loots, Du Toit AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), 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 N-alkyl quinolone; decoquinate derivative RMB041, has recently shown promising antimicrobial activity against Mtb, 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 Mtb treated with decoquinate derivative RMB041 by comparison to non-treated Mtb controls. The most significantly altered pathways in Mtb 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 Mtb. Additionally, we identified metabolic changes suggesting inhibition of protein synthesis and a state of dormancy. DA - 2021-06-10 DB - OpenUCT DP - University of Cape Town IS - 6 J1 - Antibiotics LK - https://open.uct.ac.za PY - 2021 T1 - Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics TI - Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics UR - http://hdl.handle.net/11427/35365 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/35365
dc.identifier.vancouvercitationKnoll KE, Lindeque Z, Adeniji AA, Oosthuizen CB, Lall N, Loots DT. Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics. Antibiotics. 2021;10(6):693. http://hdl.handle.net/11427/35365.en_ZA
dc.publisher.departmentBiological Sciences
dc.publisher.facultyFaculty of Science
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceAntibioticsen_US
dc.sourceAntibiotics
dc.source.journalissue6
dc.source.journalvolume10
dc.source.pagination693
dc.source.urihttp://www.mdpi.com/journal/antibiotics
dc.titleElucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomicsen_US
dc.typeJournal Articleen_US
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
antibiotics-10-00693.pdf
Size:
1.32 MB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
0 B
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Journal Articles