Structural features of the arabinan component of the lipoarabinomannan of Mycobacterium tuberculosis

Chatterjee, Delphi; Bozic, C M; McNeil, Michael; Brennan, Patrick J.

doi:10.1016/s0021-9258(18)92870-x

Cited by 150 publications

(39 citation statements)

References 17 publications

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“…These indicate a strong upregulated synthesis towards cell wall repair [37] and an accumulation thereof due to DQ derivative RMB041 inhibiting this process, which strengthens previous findings, suggesting the antimycobacterial activity of DQ derivative RMB041 targeting the cell wall [25]. The distinctly multilaminate cell wall of Mtb consists of a peptidoglycan (PG) layer covalently attached to arabinogalactan (AG) [38], which itself attaches to mycolic acids. Interspersed is the mycobacterial plasma membrane, consisting of glycerophospholipids and glycerolipids, phosphatidyl myo-inositol mannosides (PIM), lipomannans (LM), and lipoarabinomannans (LAM) [39], all of which are considered critical for maintaining cell wall integrity [40], and PIM, which contributes to the low permeability of the cell envelope and intrinsic tolerance to antibiotics [41].…”

Section: Discussionsupporting

confidence: 81%

“…The saturated fatty acids identified in this study are synthesized by fatty acid synthase type I (FAS I) and provide fatty acylcoenzyme A's (CoA) to FAS II for elongation [45]. FAS I and FAS II provide acyl-groups for the synthesis of all cell wall components except for AG [38,46,47]. C14:0, C16:0, C18:0, ∆ 9 C16:1, and ∆ 9 C18:1 are considered major fatty acids of the glycerolipids and mycolic acids [48][49][50].…”

Section: Discussionmentioning

confidence: 93%

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

et al. 2021

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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.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 93%

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

et al. 2021

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“…These indicate a strongly upregulated synthesis towards cell wall repair, supporting previous evidence associating ciprofloxacin with cell wall damage [47]. Simplified, lying outside of the cytoplasmic membrane, a peptidoglycan (PG) layer is covalently attached to arabinogalactan (AG), which itself attaches to mycolic acids (MA), to form the MA-AG-PG complex (MAPc) [77,78]. Interspersed within the MAPc, are the glycerolipids, phosphatidyl myo-inositol mannosides (PIM) and lipoarabinomannans (LAM) [79].…”

Section: Discussionsupporting

confidence: 76%

Elucidating the antimycobacterial mechanism of action of ciprofloxacin using metabolomics

Knoll¹,

Lindeque²,

Adetomiwa³

et al. 2021

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In the interest of developing more effective and safer anti-Tuberculosis treatment, we aimed for a better understanding of the antimycobacterial action of ciprofloxacin against Mycobacterium tuberculosis (Mtb). We used GCxGC-TOF-MS and well described metabolomics statistical approaches, to investigate and compare the metabolic profiles of Mtb in the presence and absence of the drug. The metabolites that best describe the differences between the compared groups were identified as markers characterizing the changes induced by ciprofloxacin. Malic acid was ranked as the most significantly altered metabolite marker induced by ciprofloxacin, indicative of an inhibition of the tricarboxylic acid (TCA) and glyoxylate cycle of Mtb. The altered fatty acid, myo-inositol and triacylglycerol metabolism seen in this group, supports the previous observations of ciprofloxacin action on the Mtb cell wall. Furthermore, the altered pentose phosphate intermediates, glycerol metabolism markers, glucose accumulation, and the reduction in the glucogenic amino acids specifically, indicates a flux towards DNA (as well as cell wall) repair, also supporting previous findings of DNA damage caused by ciprofloxacin. This study further provides insights useful for designing network whole-system strategies for the identification of possible modes of actions of various drugs and possibly adaptations by Mtb resulting in resistance.

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“…These indicate a strongly upregulated synthesis toward cell wall repair, supporting previous evidence associating ciprofloxacin with cell wall damage [47]. Simplified, lying outside of the cytoplasmic membrane, a peptidoglycan (PG) layer is covalently attached to arabinogalactan (AG), which itself attaches to mycolic acids (MA) to form the MA-AG-PG complex (MAPc) [77,78]. Interspersed within the MAPc, are the glycerolipids, phosphatidyl myo-inositol mannosides (PIM) and lipoarabinoman-nans (LAM) [79].…”

Section: Discussionsupporting

confidence: 75%

Elucidating the Antimycobacterial Mechanism of Action of Ciprofloxacin Using Metabolomics

et al. 2021

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In the interest of developing more effective and safer anti-tuberculosis drugs, we used a GCxGC-TOF-MS metabolomics research approach to investigate and compare the metabolic profiles of Mtb in the presence and absence of ciprofloxacin. The metabolites that best describe the differences between the compared groups were identified as markers characterizing the changes induced by ciprofloxacin. Malic acid was ranked as the most significantly altered metabolite marker induced by ciprofloxacin, indicative of an inhibition of the tricarboxylic acid (TCA) and glyoxylate cycle of Mtb. The altered fatty acid, myo-inositol, and triacylglycerol metabolism seen in this group supports previous observations of ciprofloxacin action on the Mtb cell wall. Furthermore, the altered pentose phosphate intermediates, glycerol metabolism markers, glucose accumulation, as well as the reduction in the glucogenic amino acids specifically, indicate a flux toward DNA (as well as cell wall) repair, also supporting previous findings of DNA damage caused by ciprofloxacin. This study further provides insights useful for designing network whole-system strategies for the identification of possible modes of action of various drugs and possibly adaptations by Mtb resulting in resistance.

show abstract

Structural features of the arabinan component of the lipoarabinomannan of Mycobacterium tuberculosis

Cited by 150 publications

References 17 publications

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

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

Elucidating the antimycobacterial mechanism of action of ciprofloxacin using metabolomics

Elucidating the Antimycobacterial Mechanism of Action of Ciprofloxacin Using Metabolomics

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